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HAZEL SIVE: All
right, moving along,

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00:00:30,750 --> 00:00:32,975
I want to talk about
three things today.

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The first is breaking
symmetry in the embryo,

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00:00:48,340 --> 00:00:51,380
leading to the first
differences that then go on

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00:00:51,380 --> 00:00:56,060
to amplify into many differences
in a multicellular organism.

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00:00:56,060 --> 00:01:05,120
And then I'm going to talk
about organic genesis and then

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00:01:05,120 --> 00:01:07,670
about morphogenesis.

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00:01:07,670 --> 00:01:10,250
And we'll define these
terms as we go along.

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00:01:14,760 --> 00:01:19,755
Let's start with this
question of breaking symmetry.

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00:01:23,370 --> 00:01:28,260
And I'm going to
start by going back

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to the last handout
of last lecture

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00:01:33,390 --> 00:01:35,740
that you should have looked at--

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00:01:35,740 --> 00:01:41,100
hm, I wonder if our AV
expert could do something

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to the screen.

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I don't think it's the computer.

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00:01:43,320 --> 00:01:44,520
I think it's the screens.

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00:01:44,520 --> 00:01:45,780
Let's see if we can do this.

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00:01:48,940 --> 00:01:54,790
The last handout I gave
you was a consideration

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of how different parts of
the embryo become different.

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00:01:57,732 --> 00:02:00,190
And I started off-- and you
might have this in front of you

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00:02:00,190 --> 00:02:00,690
still--

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00:02:00,690 --> 00:02:04,000
I started off with an
embryo, a fertilized egg,

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00:02:04,000 --> 00:02:08,335
that's got some kind
of asymmetry to it.

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00:02:08,335 --> 00:02:12,320
And I've called
it a determinant.

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00:02:12,320 --> 00:02:15,770
And at the first
cell division, look,

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00:02:15,770 --> 00:02:18,710
I've put that
determinant into one cell

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00:02:18,710 --> 00:02:21,020
and not the other cell.

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00:02:21,020 --> 00:02:24,500
One cell and not the other cell.

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00:02:24,500 --> 00:02:28,040
Now, let's say that
that determinant has

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00:02:28,040 --> 00:02:31,370
some effect on changing
the secreted factors--

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00:02:31,370 --> 00:02:33,350
oh, fantastic,
thank you very much.

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00:02:33,350 --> 00:02:39,970
It's like magic-- that
determinant has an effect.

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00:02:39,970 --> 00:02:46,090
And it actually elicits signals
to be secreted from the cell.

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00:02:46,090 --> 00:02:48,010
Then look what happens
at the next stage,

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00:02:48,010 --> 00:02:51,760
at the four cell stage,
here is a cell that's

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00:02:51,760 --> 00:02:53,440
secreting a signal.

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00:02:53,440 --> 00:02:56,850
And it's doing something to the
cell that receives the signal.

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00:02:56,850 --> 00:02:58,900
It's making it brown.

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00:02:58,900 --> 00:03:03,010
And that signal in turn
then elicits other signals.

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00:03:03,010 --> 00:03:04,990
So the brown cells
start signaling

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00:03:04,990 --> 00:03:06,280
to the cell next door.

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00:03:06,280 --> 00:03:10,810
And as cell division precedes,
you now get gray cell.

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00:03:10,810 --> 00:03:13,840
And this is a
theoretical, but a real,

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00:03:13,840 --> 00:03:18,760
demonstration of how the embryo
becomes different over time,

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00:03:18,760 --> 00:03:21,250
starting with an
initial asymmetry.

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00:03:21,250 --> 00:03:24,550
That is then built
upon due to segregation

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00:03:24,550 --> 00:03:28,990
of localized factors and also
due to cell-cell signaling.

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00:03:28,990 --> 00:03:31,420
And all of this comes
together to make

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00:03:31,420 --> 00:03:34,630
these different regions, which
I've cool territories, which

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00:03:34,630 --> 00:03:36,460
eventually will
go on to give rise

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to different kinds of cells
or different groups of kinds

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00:03:40,750 --> 00:03:43,140
of cells.

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00:03:43,140 --> 00:03:45,180
If you look in a real embryo--

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this is a fruit fly
embryo, Drosophila embryo.

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You don't have a handout.

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Just look on the screen.

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You can see the
sequential division.

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00:03:53,670 --> 00:03:56,970
And you can see this by looking
at changes in gene expression

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patterns.

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And it's really spectacular.

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This is a drawing.

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00:04:00,320 --> 00:04:01,740
But you can actually
look at this

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00:04:01,740 --> 00:04:03,810
in terms of in
situ hybridization,

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that technique I
mentioned last time,

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where one can look at
where RNAs or proteins,

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and in the case of in
situ hybridization,

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it's RNA, where
RNAs are localized.

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00:04:14,610 --> 00:04:16,459
And in the very
early embryo, there

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is an asymmetry of
a protein called

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bicoid, where there's more
on one side than the other.

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A little later,
after fertilization,

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you start to see literally
these stripes of RNA

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or protein across the embryo.

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And then the stripes of
different proteins and RNA

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get narrower as the embryo is
divided up into its segments

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and so on.

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And so what you see out of this
is the embryo being divided up

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from one large territory
into smaller and smaller

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00:04:48,610 --> 00:04:49,720
territories.

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00:04:49,720 --> 00:04:52,225
But the question is,
where does it all start?

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And so the first asymmetry
has got something

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00:05:06,210 --> 00:05:09,770
to do with fertilization.

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00:05:09,770 --> 00:05:27,130
It can either occur before,
at, or after fertilization,

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00:05:27,130 --> 00:05:36,010
where the haploid egg and
sperm fuse to become a zygote.

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00:05:36,010 --> 00:05:41,930
And somewhere in this process,
this asymmetry develops.

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00:05:41,930 --> 00:05:45,640
In the case of frogs,
the first asymmetries

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are formed before fertilization,
and also in Drosophila, fruit

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00:05:49,591 --> 00:05:50,090
flies.

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00:05:53,510 --> 00:05:58,820
In the case of
Caenorhabditis, also

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00:05:58,820 --> 00:06:04,430
known as the worm, asymmetry
forms at fertilization.

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00:06:04,430 --> 00:06:08,840
And in the case of mammals,
like ourselves, the asymmetries

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00:06:08,840 --> 00:06:11,010
appear to form of
to fertilization.

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00:06:15,390 --> 00:06:18,690
And these asymmetries
eventually build up

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00:06:18,690 --> 00:06:22,110
to give rise to a system
of positional coordinates,

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kind of like the lines
of latitude and longitude

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on the globe.

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And these are called the axes,
which are positional values.

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00:06:47,710 --> 00:06:50,020
And there are three of them.

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00:06:50,020 --> 00:06:52,540
I'm just going to put the
initials on the board.

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00:06:52,540 --> 00:06:55,720
And then I'll show you a slide,
and you can get these later.

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00:06:55,720 --> 00:07:01,360
They're called a
A/P, D/V, and L/R.

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00:07:01,360 --> 00:07:04,450
And if you look on
the screen, you'll

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00:07:04,450 --> 00:07:08,230
see my diagram of a mouse,
the same in ourselves,

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00:07:08,230 --> 00:07:11,710
where there is this
A/P coordinate, which

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00:07:11,710 --> 00:07:16,420
stands for anteroposterior,
where antero is the head

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00:07:16,420 --> 00:07:20,950
and posterior is the tail, or
as far back as your body goes.

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00:07:20,950 --> 00:07:25,870
Then there's dorsal which refers
to back and ventral, belly.

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00:07:25,870 --> 00:07:28,330
And then there's left and right.

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00:07:28,330 --> 00:07:32,290
And these values are
kind of like north,

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00:07:32,290 --> 00:07:35,530
south, east, west,
and then degrees

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00:07:35,530 --> 00:07:38,570
on either side of the meridian.

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They help the embryo
figure out where

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00:07:40,910 --> 00:07:44,030
to put different organs
in different cell types.

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00:07:44,030 --> 00:07:46,550
And I'm not going to dwell on
them in the interest of time,

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00:07:46,550 --> 00:07:48,110
but there are a
whole sets of genes

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00:07:48,110 --> 00:07:51,890
that are involved in setting
up these coordinates.

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The one thing that
I will dwell on more

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00:07:54,890 --> 00:07:57,050
is a specific
example of setting up

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00:07:57,050 --> 00:08:15,210
the first asymmetry
in Caenorhabditis,

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where this first asymmetry
is set up at fertilization.

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00:08:18,990 --> 00:08:21,480
And the bottom line-- we'll
look on it on your hand out

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00:08:21,480 --> 00:08:22,620
in a moment--

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00:08:22,620 --> 00:08:33,419
is that the sperm entry and
particularly the centriole

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00:08:33,419 --> 00:08:42,010
brought in by the sperm
causes a massive rearrangement

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00:08:42,010 --> 00:08:46,750
of the cytoskeleton in
the egg or in the zygote.

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00:08:46,750 --> 00:08:50,710
The cytoskeleton we mentioned
way back in Lecture 2.

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It is the system of actin,
filaments, and microtubule

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00:08:55,930 --> 00:08:59,440
tubules that give the
cell shape and allow it,

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00:08:59,440 --> 00:09:02,890
as we'll discuss later
on, to move and to help

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00:09:02,890 --> 00:09:05,800
build the animal or the plant.

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00:09:05,800 --> 00:09:15,050
So this the sperm entry causes
cytoskeletal re-arrangement.

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00:09:21,230 --> 00:09:29,730
And this particularly pertains
to actin and tubulin, where

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00:09:29,730 --> 00:09:36,620
the tubulin forms
microtubules and the actin

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00:09:36,620 --> 00:09:39,605
forms microfilaments.

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00:09:46,820 --> 00:09:49,760
And with the cytoskeletal
re-arrangement,

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00:09:49,760 --> 00:09:53,240
a protein called Par
6, that is firmly

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00:09:53,240 --> 00:09:57,170
attached to the
cytoskeleton, is pulled

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00:09:57,170 --> 00:10:02,200
to one side of the zygote,
leaving one side of the zygote

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00:10:02,200 --> 00:10:06,240
with lots of par-6 on
the other side with none.

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00:10:06,240 --> 00:10:10,360
And at the first cell division,
one cell gets lots of Par 6,

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00:10:10,360 --> 00:10:11,920
and the other gets none.

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00:10:11,920 --> 00:10:14,290
And that gives you
your first asymmetry

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00:10:14,290 --> 00:10:16,810
upon which the embryo
builds to give rise

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00:10:16,810 --> 00:10:19,850
to all its different
cell types and organs.

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00:10:19,850 --> 00:10:25,480
So the cytoskeletal
re-arrangement pulls

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00:10:25,480 --> 00:10:31,708
the attached Par 6 protein--

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and this is a
regulatory protein.

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It doesn't matter
exactly what it does--

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00:10:44,530 --> 00:10:54,060
to the future anterior
side of the embryo.

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And in doing so, it actually
sets up the anterior side

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of the embryo.

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Let's look at your first
slide or your first handout.

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00:11:06,070 --> 00:11:10,130
This is a diagram of
the early worm egg,

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00:11:10,130 --> 00:11:12,260
actually the very
early worm zygote,

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00:11:12,260 --> 00:11:16,510
because here is the egg
nucleus, called a pronucleus.

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00:11:16,510 --> 00:11:18,200
It's haploid.

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00:11:18,200 --> 00:11:21,370
The sperm pronucleus
has just entered.

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And the cytoskeleton I've
represented by this grid.

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00:11:25,160 --> 00:11:29,050
And Par 6 protein is
represented by the red

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00:11:29,050 --> 00:11:31,910
that you can see on
the screen surrounding

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the outside of the zygote.

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00:11:36,170 --> 00:11:41,120
Here's the sperm entry, causing
cytoskeletal contraction.

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00:11:41,120 --> 00:11:46,260
And with it, because par-6 is
attached to the cytoskeleton,

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00:11:46,260 --> 00:11:50,090
Par 6 is moved to
one side of the cell.

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00:11:50,090 --> 00:11:52,100
That's the most important thing.

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Later on, the first
cell division along this

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00:11:55,760 --> 00:11:57,630
dotted line here.

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00:11:57,630 --> 00:12:01,040
And you can see that the
first cell, in the first cell

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00:12:01,040 --> 00:12:04,280
division, one of the cells
would get most of the Par 6

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00:12:04,280 --> 00:12:07,650
and the other cell
would get very little.

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00:12:07,650 --> 00:12:09,360
This is a very
beautiful mechanism

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00:12:09,360 --> 00:12:13,020
that's been worked out
really beautifully in worms.

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Here's a movie that I
guess isn't going to work.

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00:12:19,190 --> 00:12:21,020
You know what, it
was working great

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00:12:21,020 --> 00:12:22,310
before I walked in this room.

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00:12:22,310 --> 00:12:23,490
But it's not going to work.

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00:12:23,490 --> 00:12:25,870
So I'm going to
post it as a movie.

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00:12:25,870 --> 00:12:28,710
And you can go to the
URL and you can get it.

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00:12:28,710 --> 00:12:30,590
And you'll see what
this movie does

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00:12:30,590 --> 00:12:33,680
will show you fluorescently
labeled Par protein.

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00:12:33,680 --> 00:12:36,350
It's actually a different
protein than Par 6.

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00:12:36,350 --> 00:12:38,900
And you'll be able to
see it moving beautifully

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00:12:38,900 --> 00:12:41,350
to one side of the
embryo and not the other.

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00:12:51,570 --> 00:12:56,410
Number 2, organogenesis.

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00:13:08,940 --> 00:13:14,060
An organ, as I've
written on the screen,

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00:13:14,060 --> 00:13:17,570
is a functional unit
of many cell types

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00:13:17,570 --> 00:13:22,490
that are arranged
obligatorily in

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00:13:22,490 --> 00:13:24,710
a three-dimensional
structure that allows

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00:13:24,710 --> 00:13:27,260
them to function together.

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00:13:27,260 --> 00:13:32,900
So the problem we have here
is that an organ is many cell

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00:13:32,900 --> 00:13:46,940
types, arranged in
3-D, such that there

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00:13:46,940 --> 00:13:51,830
is a specific
functional outcome,

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00:13:51,830 --> 00:13:55,940
like the heart pumps blood,
the kidney filters blood,

201
00:13:55,940 --> 00:13:58,280
the eyes see.

202
00:13:58,280 --> 00:14:02,360
All of these things require
both of these correct cell

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00:14:02,360 --> 00:14:04,670
types and 3-D organization.

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00:14:04,670 --> 00:14:08,600
And just this sentence
or just this phrase

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00:14:08,600 --> 00:14:12,350
raises two questions.

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00:14:12,350 --> 00:14:15,200
How do you get all the cell
types to the correct place?

207
00:14:32,130 --> 00:14:34,200
And how are they put into
the correct structure?

208
00:14:56,180 --> 00:15:00,080
Let's phrase the problem
by looking at the kidney.

209
00:15:00,080 --> 00:15:05,690
The kidney is one of
the most complex organs.

210
00:15:05,690 --> 00:15:07,050
It does two things.

211
00:15:07,050 --> 00:15:10,400
It filters the blood and
gets waste products out

212
00:15:10,400 --> 00:15:12,860
of the blood,
particularly products

213
00:15:12,860 --> 00:15:15,810
of amino acid metabolism.

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00:15:15,810 --> 00:15:18,830
And it also maintains
water balance.

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00:15:18,830 --> 00:15:20,780
Both of those things
are crucial functions

216
00:15:20,780 --> 00:15:25,220
of that kidney, which consists
of about 15 different cell

217
00:15:25,220 --> 00:15:29,210
types, which are connected
into several types of tubes

218
00:15:29,210 --> 00:15:32,010
that lead on fluidly
from one to the next.

219
00:15:32,010 --> 00:15:34,730
You have one type of
tube that does one thing.

220
00:15:34,730 --> 00:15:36,560
It's connected to
the next tube, which

221
00:15:36,560 --> 00:15:40,220
does the next thing, connected
to the next tube and so on.

222
00:15:40,220 --> 00:15:42,020
The tubes are very long.

223
00:15:42,020 --> 00:15:44,120
They form a 3-D organization.

224
00:15:44,120 --> 00:15:46,760
And they form filtration
units, called nephrons.

225
00:15:46,760 --> 00:15:48,890
Here are part of the nephrons.

226
00:15:48,890 --> 00:15:51,860
And you just have to look at
this without any knowledge

227
00:15:51,860 --> 00:15:54,080
to see that this is
a complex structure.

228
00:15:57,150 --> 00:16:01,120
This is a distant view, so
you can't see the cells here.

229
00:16:01,120 --> 00:16:03,450
Low magnification structure.

230
00:16:03,450 --> 00:16:05,460
This is a really complex organ.

231
00:16:05,460 --> 00:16:09,810
And it takes a moment's
thought to wonder how something

232
00:16:09,810 --> 00:16:11,830
like this gets put together.

233
00:16:11,830 --> 00:16:14,360
And, of course, this is not
only important for developments.

234
00:16:14,360 --> 00:16:17,160
It's important for thinking
about how you would replace

235
00:16:17,160 --> 00:16:20,510
someone's kidney with
something that was artificial,

236
00:16:20,510 --> 00:16:24,130
and not just using
donated organs.

237
00:16:24,130 --> 00:16:26,460
Could you build
something like a kidney

238
00:16:26,460 --> 00:16:30,640
and use it in place
of donated organs?

239
00:16:30,640 --> 00:16:33,960
So the question of organogenesis
is of huge importance

240
00:16:33,960 --> 00:16:38,130
both to basic researches,
to physicians trying

241
00:16:38,130 --> 00:16:41,100
to understand what goes
wrong when organs fail,

242
00:16:41,100 --> 00:16:44,310
and to bioengineers who are
trying to build organs that

243
00:16:44,310 --> 00:16:45,660
would replace human versions.

244
00:16:49,080 --> 00:16:51,510
Let's start by tackling
the first question.

245
00:16:51,510 --> 00:16:56,520
How do you put different cell
types in the correct place?

246
00:16:56,520 --> 00:16:58,860
And there are three
possibilities, all of which

247
00:16:58,860 --> 00:17:00,080
are used by the body.

248
00:17:19,790 --> 00:17:23,460
OK, so one, they can move there.

249
00:17:23,460 --> 00:17:26,500
There can be all these cell
types all over the body.

250
00:17:26,500 --> 00:17:29,490
And they can say, oh, OK,
we need to go move over here

251
00:17:29,490 --> 00:17:31,630
to build a kidney.

252
00:17:31,630 --> 00:17:34,780
OK, it seems unlikely,
but in fact, it's true.

253
00:17:34,780 --> 00:17:40,240
And that process
would be migration,

254
00:17:40,240 --> 00:17:43,090
where the cells come
from all over the place

255
00:17:43,090 --> 00:17:44,800
to build the organ.

256
00:17:44,800 --> 00:17:46,645
The cells need to
know where to go.

257
00:17:53,850 --> 00:17:57,090
And that just pushes
the problem back one.

258
00:17:57,090 --> 00:18:01,650
But the great example of
cell migration is the limb.

259
00:18:01,650 --> 00:18:04,500
Most of the cells in
your limbs and mine

260
00:18:04,500 --> 00:18:07,800
did not come right from
where the limb grew.

261
00:18:07,800 --> 00:18:10,380
They migrated there
from the spinal cord.

262
00:18:10,380 --> 00:18:12,360
They migrated there
from the muscles

263
00:18:12,360 --> 00:18:14,880
on the sides of the body.

264
00:18:14,880 --> 00:18:18,360
And the blood vessels also
grew in from the cells

265
00:18:18,360 --> 00:18:20,450
that were distant.

266
00:18:20,450 --> 00:18:28,030
So the limb puts it all
together by moving cells around.

267
00:18:28,030 --> 00:18:30,480
How else could you get
cells to the right place?

268
00:18:37,730 --> 00:18:38,710
See, it's not so easy.

269
00:18:38,710 --> 00:18:40,710
OK, so here's another one.

270
00:18:40,710 --> 00:18:45,240
Well, you could in one place
tell a bunch of different cells

271
00:18:45,240 --> 00:18:47,710
to form at the same time.

272
00:18:47,710 --> 00:18:50,080
You could have your
organ and say, all right,

273
00:18:50,080 --> 00:18:53,790
we need cell types 1 to 10.

274
00:18:53,790 --> 00:18:54,710
Form.

275
00:18:54,710 --> 00:18:55,780
Here's some signals.

276
00:18:55,780 --> 00:18:57,730
You will form in this one place.

277
00:18:57,730 --> 00:18:59,620
And in fact that happens.

278
00:18:59,620 --> 00:19:06,340
This is called
co-induction, where

279
00:19:06,340 --> 00:19:17,040
many cell types or several
cell types form in one place,

280
00:19:17,040 --> 00:19:23,550
often because one signal can
act at different concentrations

281
00:19:23,550 --> 00:19:26,010
to give rise to
different cell types.

282
00:19:26,010 --> 00:19:28,980
So many cell types
form in one place,

283
00:19:28,980 --> 00:19:37,980
often due to a concentration
gradient of an inducer,

284
00:19:37,980 --> 00:19:38,505
of a signal.

285
00:19:48,300 --> 00:19:56,400
And the great example of this is
the spinal cord, and the nerves

286
00:19:56,400 --> 00:20:01,260
in the spinal cord, which arise
by co-induction of actually

287
00:20:01,260 --> 00:20:05,060
about two different inducers.

288
00:20:05,060 --> 00:20:10,580
And the third one is called
sequential induction.

289
00:20:10,580 --> 00:20:19,540
And this is how
the kidneys forms,

290
00:20:19,540 --> 00:20:22,180
where the idea with
sequential induction

291
00:20:22,180 --> 00:20:24,760
is that a cell type forms.

292
00:20:24,760 --> 00:20:28,780
And it says, OK, I need this
other cell type to work with.

293
00:20:28,780 --> 00:20:30,670
And it instructs
the cells around

294
00:20:30,670 --> 00:20:32,680
to become another cell type.

295
00:20:32,680 --> 00:20:35,890
And those cells in turn might
instruct some cells around them

296
00:20:35,890 --> 00:20:37,690
to become another cell type.

297
00:20:37,690 --> 00:20:39,370
And there's this
conversation going

298
00:20:39,370 --> 00:20:43,870
on sequentially in the place
where the organ will form.

299
00:20:43,870 --> 00:20:56,590
So cell type 1
induces or signals

300
00:20:56,590 --> 00:21:07,390
to type 2, which
induces type 3, etc.

301
00:21:07,390 --> 00:21:12,730
And a great example
of this is the kidney,

302
00:21:12,730 --> 00:21:17,470
where I will say it is still not
known how you build a kidney.

303
00:21:17,470 --> 00:21:18,970
Some of the steps
are understood.

304
00:21:18,970 --> 00:21:20,920
But there's no
organ where we can

305
00:21:20,920 --> 00:21:23,080
say these are all the
steps that build the organ.

306
00:21:23,080 --> 00:21:24,160
It's incredibly complex.

307
00:21:27,910 --> 00:21:30,460
Good.

308
00:21:30,460 --> 00:21:33,340
That's all I'm going to say
about organogenesis, to throw

309
00:21:33,340 --> 00:21:35,860
out at your this
complex problem.

310
00:21:35,860 --> 00:21:38,920
And you can explore it
more in later courses.

311
00:21:38,920 --> 00:21:42,460
I am going to talk more, though,
about this question of 3D

312
00:21:42,460 --> 00:21:43,150
structure.

313
00:21:48,420 --> 00:21:50,772
And that is the question
of morphogenesis.

314
00:21:59,780 --> 00:22:02,740
Oranogenesis,
morphogenesis, you might

315
00:22:02,740 --> 00:22:06,220
have heard of histogenesis,
which means building tissues.

316
00:22:06,220 --> 00:22:09,160
The genesis part
refers to building.

317
00:22:09,160 --> 00:22:12,700
That's what it means,
building of something.

318
00:22:12,700 --> 00:22:21,040
Morphogenesis, building a
three-dimensional structure,

319
00:22:21,040 --> 00:22:31,570
or the generation of
form is what you'll see.

320
00:22:31,570 --> 00:22:37,320
And what that really means
is building 3D structure.

321
00:22:44,510 --> 00:22:46,880
And this relates
to organogenesis

322
00:22:46,880 --> 00:22:49,400
because in organogenesis
one of the things that's

323
00:22:49,400 --> 00:22:52,670
hidden on the board
above was the question

324
00:22:52,670 --> 00:23:01,453
of getting cells of an organ
into the correct 3D structure.

325
00:23:12,810 --> 00:23:16,380
And, of course, this
question of 3D structure

326
00:23:16,380 --> 00:23:18,930
is intuitively quite clear.

327
00:23:18,930 --> 00:23:22,740
You can imagine a
human heart or having

328
00:23:22,740 --> 00:23:25,260
some kind of animal's
heart in front of you.

329
00:23:25,260 --> 00:23:27,210
It's an extraordinary structure.

330
00:23:27,210 --> 00:23:29,930
It's actually a folded tube,
where the walls of the tube

331
00:23:29,930 --> 00:23:31,780
have become very muscular.

332
00:23:31,780 --> 00:23:35,100
And the heart will pump
with great regularity.

333
00:23:35,100 --> 00:23:38,700
It's a controlled pump that can
speed up or slow down depending

334
00:23:38,700 --> 00:23:42,320
on the how the animal is doing.

335
00:23:42,320 --> 00:23:47,240
And that heart contains about
10 different kinds of cells.

336
00:23:47,240 --> 00:23:49,940
And you can imagine having
one in front of you.

337
00:23:49,940 --> 00:23:51,860
And you can imagine
my coming along

338
00:23:51,860 --> 00:23:54,890
with some kind of
protease or calcium

339
00:23:54,890 --> 00:23:58,010
free medium that will cause
the cells of the heart

340
00:23:58,010 --> 00:24:02,490
to leave one
another, deconstruct

341
00:24:02,490 --> 00:24:03,760
the structure of the heart.

342
00:24:03,760 --> 00:24:06,510
Now you've got a heart
that's not this pump looking

343
00:24:06,510 --> 00:24:07,920
tube structure.

344
00:24:07,920 --> 00:24:09,840
It's a pile of cells.

345
00:24:09,840 --> 00:24:13,552
The same cells that were in
the organ of the heart, but,

346
00:24:13,552 --> 00:24:14,510
of course, they're not.

347
00:24:14,510 --> 00:24:16,110
They're just a pile of cells.

348
00:24:16,110 --> 00:24:16,950
They're all there.

349
00:24:16,950 --> 00:24:18,780
They might all be alive.

350
00:24:18,780 --> 00:24:20,370
But they're not acting.

351
00:24:20,370 --> 00:24:22,780
And that's really an
engineering problem,

352
00:24:22,780 --> 00:24:24,790
which is what
morphogenesis is all about.

353
00:24:24,790 --> 00:24:27,390
And I want to just discuss
morphogenesis with you

354
00:24:27,390 --> 00:24:33,180
because I think as a science
and engineering problem,

355
00:24:33,180 --> 00:24:36,100
it's really an extraordinary
one to think about.

356
00:24:36,100 --> 00:24:38,880
And it's extraordinary to think
about because really there's

357
00:24:38,880 --> 00:24:41,550
only one building
material by which all

358
00:24:41,550 --> 00:24:46,440
the structures of all organisms
are built. And that's cells.

359
00:24:46,440 --> 00:24:49,650
You can't find different
plastics or different metals

360
00:24:49,650 --> 00:24:52,410
or different alloys
to build things with,

361
00:24:52,410 --> 00:24:54,420
it's just one building material.

362
00:24:54,420 --> 00:24:56,940
And it's really
amazing what life

363
00:24:56,940 --> 00:24:59,130
has managed to do with cells.

364
00:24:59,130 --> 00:25:02,290
And that's what we'll explore
for the rest of the lecture.

365
00:25:02,290 --> 00:25:06,540
So getting cells in organs
into the correct 3D structure.

366
00:25:09,900 --> 00:25:16,500
This is a great example of
3D structure, another one,

367
00:25:16,500 --> 00:25:21,540
the lungs, which are about a
20-fold iteration of branching.

368
00:25:21,540 --> 00:25:25,470
You start off with one
tube, the trachea, which

369
00:25:25,470 --> 00:25:28,200
branches into the two bronchi.

370
00:25:28,200 --> 00:25:31,470
And those branch and they
branch and they branch.

371
00:25:31,470 --> 00:25:33,900
It's about a 20-fold branching.

372
00:25:33,900 --> 00:25:37,020
And you end up with
many, many little tubes.

373
00:25:37,020 --> 00:25:39,850
In this rendition,
the ends of the tubes,

374
00:25:39,850 --> 00:25:42,660
which are sacs of cells,
have been taken away.

375
00:25:42,660 --> 00:25:45,870
But it's through these tubes
that oxygen moves or air moves.

376
00:25:45,870 --> 00:25:49,140
The oxygen is extracted
from the air, moves

377
00:25:49,140 --> 00:25:54,090
into the bloodstream, and
then the waste air is exhaled.

378
00:25:54,090 --> 00:25:55,530
And the same thing starts again.

379
00:25:55,530 --> 00:25:59,190
How do you build these lungs
with this branching arrangement

380
00:25:59,190 --> 00:25:59,774
of cells?

381
00:25:59,774 --> 00:26:01,440
And indeed, how do
you build the kidney?

382
00:26:06,210 --> 00:26:10,910
You know, the problem
really phrases like this--

383
00:26:10,910 --> 00:26:15,290
and if we had more time today,
I would sit and challenge you

384
00:26:15,290 --> 00:26:17,630
for five or 10 minutes
to go and think

385
00:26:17,630 --> 00:26:21,800
about how you take a pile of
cells from the early embryo

386
00:26:21,800 --> 00:26:23,660
and build that
structure, which could

387
00:26:23,660 --> 00:26:26,150
be what it is or
could be something

388
00:26:26,150 --> 00:26:28,450
that represents an organ.

389
00:26:28,450 --> 00:26:30,370
And while I'm moving
the boards, you

390
00:26:30,370 --> 00:26:33,520
can think about how you
would take those cells

391
00:26:33,520 --> 00:26:35,830
and turn them into
a 3D structure.

392
00:26:35,830 --> 00:26:38,571
And we'll see if we have
concordance in our thinking

393
00:26:38,571 --> 00:26:39,070
here.

394
00:26:53,000 --> 00:26:55,400
All right, so let's
turn this pile of cells

395
00:26:55,400 --> 00:26:57,140
into a 3D structure.

396
00:26:57,140 --> 00:26:58,940
And let's pull
out some processes

397
00:26:58,940 --> 00:27:02,570
that we can talk about in lay
terms, no scientific terms.

398
00:27:02,570 --> 00:27:04,370
And then I'll put
some molecular labels

399
00:27:04,370 --> 00:27:07,880
on that will help you understand
what we're talking about.

400
00:27:07,880 --> 00:27:11,450
And process indeed has two s's.

401
00:27:11,450 --> 00:27:13,990
There we go.

402
00:27:13,990 --> 00:27:16,160
Well, one thing you
know if you look

403
00:27:16,160 --> 00:27:19,040
at my pile of cells
in the 3D structure

404
00:27:19,040 --> 00:27:22,160
is that those cells
have been sorted out.

405
00:27:22,160 --> 00:27:23,810
I've put them in
different colors,

406
00:27:23,810 --> 00:27:26,240
in groups of different colors.

407
00:27:26,240 --> 00:27:29,530
So I'm going to write
that the cells sort out.

408
00:27:33,620 --> 00:27:36,470
And there is a molecular
basis for that.

409
00:27:36,470 --> 00:27:39,370
It's called homotypic
adhesion, where

410
00:27:39,370 --> 00:27:41,960
like cells tend to
bind to one another,

411
00:27:41,960 --> 00:27:43,655
so that they can
function as a unit.

412
00:27:52,470 --> 00:27:57,240
But, of course, in order to
get the cells to sort out,

413
00:27:57,240 --> 00:28:00,130
they actually had to move.

414
00:28:00,130 --> 00:28:02,260
Yes?

415
00:28:02,260 --> 00:28:04,015
Say, yes.

416
00:28:04,015 --> 00:28:04,515
OK.

417
00:28:08,220 --> 00:28:11,550
And they moved because
of their cytoskeleton,

418
00:28:11,550 --> 00:28:14,550
which was rearranging
and changing and allowing

419
00:28:14,550 --> 00:28:15,760
them to do so.

420
00:28:15,760 --> 00:28:18,390
So the molecular
basis for movement

421
00:28:18,390 --> 00:28:26,430
is cytoskeletal change
or rearrangement.

422
00:28:26,430 --> 00:28:28,680
What else is on my list?

423
00:28:28,680 --> 00:28:32,300
You know, the pile of
cells that I've got there,

424
00:28:32,300 --> 00:28:34,380
it's meant to look
loose, like it

425
00:28:34,380 --> 00:28:36,240
would be a pile of
cells that would just

426
00:28:36,240 --> 00:28:39,840
spread out all over the
table if I dumped it out.

427
00:28:39,840 --> 00:28:43,650
But the organ that I drew
is meant to look tight.

428
00:28:43,650 --> 00:28:45,990
Those cells are stuck together.

429
00:28:45,990 --> 00:28:48,100
And that is one of the
things that happens.

430
00:28:48,100 --> 00:28:50,295
The cells stick together.

431
00:28:53,560 --> 00:28:59,130
And they do so because of
cellular junctions, which

432
00:28:59,130 --> 00:29:01,920
are particular
collections of proteins

433
00:29:01,920 --> 00:29:03,940
that cause cells
to stick together,

434
00:29:03,940 --> 00:29:07,920
often in a really
waterproof kind of a way.

435
00:29:07,920 --> 00:29:09,300
The cells change shape.

436
00:29:09,300 --> 00:29:12,120
They've gone from balls
to triangles to columns.

437
00:29:18,400 --> 00:29:22,135
And that is also driven
by cytoskeletal changes.

438
00:29:30,980 --> 00:29:33,500
And then the two lost
processes on my list

439
00:29:33,500 --> 00:29:35,360
I'm not going to
explore more because we

440
00:29:35,360 --> 00:29:37,180
had a whole lecture on them.

441
00:29:37,180 --> 00:29:39,350
Cells can divide,
and they can die.

442
00:29:39,350 --> 00:29:41,210
You can get rid of
the excess cells.

443
00:29:41,210 --> 00:29:43,040
And you can generate
more cells to build

444
00:29:43,040 --> 00:29:52,130
your organ by the processes of
cell division and cell death.

445
00:29:52,130 --> 00:29:54,440
And we've had those
before, so we aren't going

446
00:29:54,440 --> 00:29:56,850
to talk about those again.

447
00:29:56,850 --> 00:30:03,380
But I will just put up cell
cycle control and apoptosis.

448
00:30:08,140 --> 00:30:08,640
Good.

449
00:30:14,592 --> 00:30:17,324
I-- yes?

450
00:30:17,324 --> 00:30:21,752
STUDENT: What about the
[INAUDIBLE] the organ,

451
00:30:21,752 --> 00:30:26,690
[INAUDIBLE]

452
00:30:26,690 --> 00:30:28,890
HAZEL SIVE: Ah, great question.

453
00:30:28,890 --> 00:30:31,970
The question is, how do
the cells know where to go?

454
00:30:31,970 --> 00:30:34,340
How do they know that
the dark blue ones

455
00:30:34,340 --> 00:30:37,670
are on the left and the columna
brown ones are on the right?

456
00:30:37,670 --> 00:30:38,990
It's a great question.

457
00:30:38,990 --> 00:30:41,070
And you know, if
we had more time,

458
00:30:41,070 --> 00:30:42,620
I think that the
thing would come up

459
00:30:42,620 --> 00:30:45,621
with was the notion
of some kind of plan,

460
00:30:45,621 --> 00:30:47,870
that there are instructions
somewhere that are telling

461
00:30:47,870 --> 00:30:49,460
the cells where to go.

462
00:30:49,460 --> 00:30:50,990
What are those instructions?

463
00:30:50,990 --> 00:30:53,660
Well, they're
somehow in the genes.

464
00:30:53,660 --> 00:30:55,910
But it's more than that.

465
00:30:55,910 --> 00:30:57,680
I don't think that
there is actually

466
00:30:57,680 --> 00:31:00,170
a set of instructions
in the genes

467
00:31:00,170 --> 00:31:03,930
that says build this organ or
the kidney or anything else.

468
00:31:03,930 --> 00:31:08,030
There's a set of
instructions that unfolds

469
00:31:08,030 --> 00:31:10,110
as the organ is being built.

470
00:31:10,110 --> 00:31:12,740
And I think what's in the
genes are the first steps

471
00:31:12,740 --> 00:31:14,390
of those instructions.

472
00:31:14,390 --> 00:31:17,180
And then they kind
of unfold bit by bit.

473
00:31:17,180 --> 00:31:19,250
So the outcome is the organ.

474
00:31:19,250 --> 00:31:21,770
And there is some
kind of a plan.

475
00:31:21,770 --> 00:31:25,760
But we don't have any evidence
that there's any kind of plan

476
00:31:25,760 --> 00:31:27,980
actually written in the genes.

477
00:31:27,980 --> 00:31:29,730
OK, it's a fascinating question.

478
00:31:29,730 --> 00:31:30,230
Good.

479
00:31:33,210 --> 00:31:35,700
Back to the toolkit.

480
00:31:35,700 --> 00:31:39,900
This toolkit to build
all organs of cells.

481
00:31:52,020 --> 00:31:54,210
But cells, you
know, are not just

482
00:31:54,210 --> 00:31:57,000
equivalent to bricks one shape.

483
00:31:57,000 --> 00:31:58,500
They can actually change.

484
00:31:58,500 --> 00:32:00,910
So it's not quite fair
that I said to you

485
00:32:00,910 --> 00:32:02,460
this is different
than engineering

486
00:32:02,460 --> 00:32:04,440
where you've only
got one material.

487
00:32:04,440 --> 00:32:06,850
It's true you've only
got one material.

488
00:32:06,850 --> 00:32:07,860
But it can change.

489
00:32:07,860 --> 00:32:11,130
It can change its shape,
and it can move around.

490
00:32:11,130 --> 00:32:14,640
And the two kinds of things
you really need to know

491
00:32:14,640 --> 00:32:21,935
are involved are single
cells and cell sheets.

492
00:32:26,240 --> 00:32:29,905
And single cells and cell sheets
are interchangeable from one

493
00:32:29,905 --> 00:32:30,405
another.

494
00:32:33,180 --> 00:32:35,875
Single cells are also
called mesenchyme.

495
00:32:40,400 --> 00:32:42,320
[INAUDIBLE] [? they ?] are.

496
00:32:42,320 --> 00:32:43,190
Single cell.

497
00:32:47,020 --> 00:32:52,920
And groups of mesenchymal
cells can associate

498
00:32:52,920 --> 00:32:55,215
to become sheets of cells.

499
00:33:00,840 --> 00:33:04,590
And these sheets are
called epithelia,

500
00:33:04,590 --> 00:33:06,480
or singular is epithelium.

501
00:33:09,970 --> 00:33:13,570
Single cells migrate.

502
00:33:13,570 --> 00:33:14,095
They move.

503
00:33:17,780 --> 00:33:20,600
And there are no junctions
between the cells that

504
00:33:20,600 --> 00:33:23,930
allows them to be single cells.

505
00:33:23,930 --> 00:33:27,650
Epithelia, cell sheets,
can change shape.

506
00:33:27,650 --> 00:33:30,890
But they don't move
around that much.

507
00:33:30,890 --> 00:33:38,570
So they change shape as sheets.

508
00:33:41,720 --> 00:33:47,115
And what that allows them to do
is to form coverings and tubes.

509
00:33:55,410 --> 00:33:58,110
I should say one
very important thing.

510
00:33:58,110 --> 00:34:00,330
The process is reversible.

511
00:34:00,330 --> 00:34:04,050
If you look at the next handout,
there is more information

512
00:34:04,050 --> 00:34:05,414
that you'll get.

513
00:34:12,239 --> 00:34:14,530
Here's your epithelial sheet.

514
00:34:14,530 --> 00:34:16,320
It's joined together
by junctions.

515
00:34:16,320 --> 00:34:19,020
Let me make a note
that there are

516
00:34:19,020 --> 00:34:21,690
junctions between the cells.

517
00:34:21,690 --> 00:34:25,093
That's what sticks the
cells together is a sheet.

518
00:34:25,093 --> 00:34:26,469
Here are the junctions.

519
00:34:26,469 --> 00:34:28,020
There are two kind.

520
00:34:28,020 --> 00:34:30,420
There's top ones
called tight junctions,

521
00:34:30,420 --> 00:34:32,014
which are waterproof junctions.

522
00:34:32,014 --> 00:34:33,389
And then they
these are the ones,

523
00:34:33,389 --> 00:34:35,535
called adhesion junctions,
which aren't so strong.

524
00:34:38,340 --> 00:34:44,100
Both epithelia and mesenchyme
sit on the extracellular

525
00:34:44,100 --> 00:34:48,900
matrix, or ECM, which
we mentioned way back,

526
00:34:48,900 --> 00:34:53,340
glycoproteins that are involved
in giving support and also

527
00:34:53,340 --> 00:34:56,800
carrying signaling
molecules to cells.

528
00:34:56,800 --> 00:35:00,840
And here is the conversion of
the sheet to the single cells,

529
00:35:00,840 --> 00:35:03,480
and the single cells
back to the sheet.

530
00:35:03,480 --> 00:35:07,950
This process of epithelial
mesenchymal transition

531
00:35:07,950 --> 00:35:10,920
or mesenchymal
epithelial transition

532
00:35:10,920 --> 00:35:13,260
is very important in cancer.

533
00:35:13,260 --> 00:35:15,480
Tumors usually start
off as epithelia.

534
00:35:15,480 --> 00:35:18,030
The And they become metastatic.

535
00:35:18,030 --> 00:35:20,140
They disperse
throughout the body

536
00:35:20,140 --> 00:35:22,290
when they become mesenchymal,
or when they give off

537
00:35:22,290 --> 00:35:25,230
single cells, which can
migrate and establish

538
00:35:25,230 --> 00:35:26,430
the tumor somewhere else.

539
00:35:26,430 --> 00:35:30,120
So this process is crucial
both in building organs

540
00:35:30,120 --> 00:35:32,700
and in cancer biology.

541
00:35:32,700 --> 00:35:34,410
The other thing that
you should note--

542
00:35:34,410 --> 00:35:36,510
we're not going to
dwell on it very much--

543
00:35:36,510 --> 00:35:40,500
is that the cells in a
sheet have got orientation.

544
00:35:40,500 --> 00:35:43,590
They've got an axis of
asymmetry along one side,

545
00:35:43,590 --> 00:35:47,730
call the apical basal axis
and an axis of asymmetry

546
00:35:47,730 --> 00:35:50,550
along the top, called
the planar axis.

547
00:35:50,550 --> 00:35:53,900
But we're not going to
dwell on that very much.

548
00:35:53,900 --> 00:36:03,950
All right, let's look
what epithelial sheets

549
00:36:03,950 --> 00:36:06,390
do in a little more detail.

550
00:36:06,390 --> 00:36:18,420
So epithelial sheets or
epithelial form waterproof

551
00:36:18,420 --> 00:36:20,070
coverings, as I've noted.

552
00:36:24,960 --> 00:36:30,210
And through cell shape changes,
they'll also bend a cell sheet

553
00:36:30,210 --> 00:36:31,710
or turn it into a tube.

554
00:36:44,320 --> 00:36:48,460
And they do this by a series
of stereotypical changes,

555
00:36:48,460 --> 00:37:01,220
where cells can change shape,
so that kind of a square cell

556
00:37:01,220 --> 00:37:09,410
can become an elongated cell in
one direction or a cell that's

557
00:37:09,410 --> 00:37:12,320
elongated in a
different direction.

558
00:37:12,320 --> 00:37:19,230
Or it can become a
wedge shaped cell.

559
00:37:19,230 --> 00:37:21,720
And the names of these
different kinds of cells

560
00:37:21,720 --> 00:37:23,130
don't really matter.

561
00:37:23,130 --> 00:37:24,330
And they're not sequential.

562
00:37:24,330 --> 00:37:28,080
So this cell can
become this cell.

563
00:37:28,080 --> 00:37:34,240
It can also become this wedge
shaped cell in one fell swoop.

564
00:37:34,240 --> 00:37:37,500
But if you think about it,
these changes in cell shape

565
00:37:37,500 --> 00:37:38,950
can do lots of things.

566
00:37:38,950 --> 00:37:42,462
For example, if cells
get long and thin,

567
00:37:42,462 --> 00:37:45,630
then the cell sheet
will lengthen.

568
00:37:45,630 --> 00:37:48,390
If cells get wedge shaped,
and you've got a whole bunch

569
00:37:48,390 --> 00:37:51,240
of them getting wedge shaped--
you can draw this out--

570
00:37:51,240 --> 00:37:53,820
you'll actually
bend the cell sheet.

571
00:37:53,820 --> 00:37:54,450
Draw it out.

572
00:37:54,450 --> 00:37:56,721
Put a whole bunch of wedge
shaped cells next to one

573
00:37:56,721 --> 00:37:57,220
another.

574
00:37:57,220 --> 00:38:00,180
And you'll see there's no
way you can get a flat sheet.

575
00:38:00,180 --> 00:38:02,400
The cell sheet bends.

576
00:38:02,400 --> 00:38:04,500
And that is one of
the things which

577
00:38:04,500 --> 00:38:07,630
drives building the
structure of organs.

578
00:38:15,100 --> 00:38:17,860
There are a lot of different
ways to make tubes.

579
00:38:17,860 --> 00:38:19,970
I've diagrammed them
on the next few slides.

580
00:38:19,970 --> 00:38:21,220
You don't have these.

581
00:38:21,220 --> 00:38:24,280
Cell sheets can roll
up to form a tube.

582
00:38:24,280 --> 00:38:27,670
Mesenchymal cells can
condense, can come together,

583
00:38:27,670 --> 00:38:29,580
to form a tube.

584
00:38:29,580 --> 00:38:31,810
And here's a really
extraordinary one.

585
00:38:31,810 --> 00:38:33,880
Single cells can form tubes.

586
00:38:33,880 --> 00:38:37,300
Tiny, single cells with
a 10 micron diameter

587
00:38:37,300 --> 00:38:39,960
can roll up on their
cell themselves

588
00:38:39,960 --> 00:38:42,250
or actually hollow
out their middles

589
00:38:42,250 --> 00:38:44,050
to become tiny, tiny tubes.

590
00:38:50,400 --> 00:38:53,070
What about single cells?

591
00:38:53,070 --> 00:38:55,380
Single cells move.

592
00:38:55,380 --> 00:38:59,540
And this allows
things to sort out

593
00:38:59,540 --> 00:39:02,720
and cells to get to
where they need to go.

594
00:39:02,720 --> 00:39:04,970
But we're also going
to use this property

595
00:39:04,970 --> 00:39:07,790
to understand the
molecular principles that

596
00:39:07,790 --> 00:39:09,590
underlies cell shape change.

597
00:39:09,590 --> 00:39:11,100
And that you should know.

598
00:39:11,100 --> 00:39:20,220
Let's make a note
that single cells move

599
00:39:20,220 --> 00:39:33,520
and that this allows cells to
sort and tissues and organs

600
00:39:33,520 --> 00:39:34,180
to form.

601
00:39:38,050 --> 00:39:40,615
And then what I'm going to tell
you over the next few slides

602
00:39:40,615 --> 00:39:44,920
and on your handouts is that
all of the movement and all

603
00:39:44,920 --> 00:39:48,130
of these shape changes
that I drew on the board

604
00:39:48,130 --> 00:39:52,330
have got to do with changing
the cytoskeleton of the cell.

605
00:39:52,330 --> 00:39:55,090
But what I'll tell
you is that it's

606
00:39:55,090 --> 00:39:58,450
about locally changing
the cytoskeleton,

607
00:39:58,450 --> 00:40:01,300
where you have to stop
viewing the cell as something

608
00:40:01,300 --> 00:40:04,540
huge, where independent
things can happen

609
00:40:04,540 --> 00:40:06,610
in different parts of the cell.

610
00:40:06,610 --> 00:40:10,270
And those independent
changes in the structure,

611
00:40:10,270 --> 00:40:13,150
in the skeleton of the
cell will get the cell

612
00:40:13,150 --> 00:40:19,880
to become long or squat
or wedge shaped or moved.

613
00:40:19,880 --> 00:40:30,800
So shape and movement of
both sheets and single cells

614
00:40:30,800 --> 00:40:37,050
is controlled by changing
the cytoskeleton.

615
00:40:46,150 --> 00:40:53,620
But it's done so locally, which
means in one part of the cell.

616
00:40:58,030 --> 00:41:03,010
And a most important change
that occurs as the cytoskeleton

617
00:41:03,010 --> 00:41:06,400
changes or with cytoskeletal
changes or is cytoskeletal

618
00:41:06,400 --> 00:41:16,130
change is a polymerization
of actin from G-actin,

619
00:41:16,130 --> 00:41:26,120
which is unpolymerized,
to F-actin--

620
00:41:26,120 --> 00:41:28,610
and this is reversible--

621
00:41:28,610 --> 00:41:33,530
which is polymerized,
non-covalently.

622
00:41:33,530 --> 00:41:39,590
And this F-actin
will stretch the cell

623
00:41:39,590 --> 00:41:41,900
and help the cell to move.

624
00:41:41,900 --> 00:41:45,200
And let's explore
that in this movie

625
00:41:45,200 --> 00:41:47,330
and in the rest
of your handouts.

626
00:41:47,330 --> 00:41:51,530
This is a movie of a
cell, where the actin has

627
00:41:51,530 --> 00:41:54,650
been labeled fluorescently.

628
00:41:54,650 --> 00:41:57,470
And what you can see
as the cell is moving

629
00:41:57,470 --> 00:42:01,080
are these little
filaments of bright green.

630
00:42:01,080 --> 00:42:04,050
Those are the
polymerized F-actin.

631
00:42:04,050 --> 00:42:07,620
And you can see if you just
focus on one, over the course

632
00:42:07,620 --> 00:42:10,920
of minutes, it goes away.

633
00:42:10,920 --> 00:42:12,960
And new ones form.

634
00:42:12,960 --> 00:42:15,960
And the new ones are
forming in the direction

635
00:42:15,960 --> 00:42:18,330
that the cell is moving.

636
00:42:18,330 --> 00:42:21,850
And this movie really
illustrates the principles

637
00:42:21,850 --> 00:42:26,760
underlying how the
cytoskeleton is controlled.

638
00:42:26,760 --> 00:42:28,410
Let's draw something
on the board

639
00:42:28,410 --> 00:42:30,600
or let's write a few
things on the board

640
00:42:30,600 --> 00:42:33,330
and then look at your
last two handouts.

641
00:42:33,330 --> 00:42:37,120
And what you'll understand is
that the principles governing

642
00:42:37,120 --> 00:42:41,890
actin polymerization are really
the same for both single cells

643
00:42:41,890 --> 00:42:44,450
and for cell sheets.

644
00:42:44,450 --> 00:42:59,710
The idea here is that the
extracellular matrix, the ECM,

645
00:42:59,710 --> 00:43:16,245
connects to the plasma membrane
via receptors on the plasma

646
00:43:16,245 --> 00:43:16,745
membrane.

647
00:43:23,510 --> 00:43:26,150
When ligands bind
these receptors,

648
00:43:26,150 --> 00:43:27,710
you know what happens now.

649
00:43:27,710 --> 00:43:30,150
Signal transduction
is activated.

650
00:43:33,680 --> 00:43:37,880
So the ligands plus
the receptors--

651
00:43:42,700 --> 00:43:46,690
and there are many
different signaling pathways

652
00:43:46,690 --> 00:43:49,270
that can be involved--

653
00:43:49,270 --> 00:43:53,170
go and activate a
cascade of things,

654
00:43:53,170 --> 00:44:10,070
which involve kinases, a
signal cascade via kinases

655
00:44:10,070 --> 00:44:12,980
and via special GTPase.

656
00:44:12,980 --> 00:44:18,095
Remember Ras was a GTPase,
but this one is called Rho.

657
00:44:26,770 --> 00:44:33,540
And Rho GPTase it's
critical in telling G-actin

658
00:44:33,540 --> 00:44:36,920
to polymerize and form F-actin.

659
00:44:36,920 --> 00:44:41,710
And so out of this
the Rho GPTase

660
00:44:41,710 --> 00:44:47,510
tells G-actin to form F actin.

661
00:44:47,510 --> 00:44:50,370
And with that,
various things happen.

662
00:44:50,370 --> 00:44:57,440
So let's look at
your last handouts.

663
00:44:57,440 --> 00:45:00,250
Here's the cell migrating.

664
00:45:00,250 --> 00:45:02,590
And the thing that
I want you to see

665
00:45:02,590 --> 00:45:05,990
is that in the
direction of migration,

666
00:45:05,990 --> 00:45:10,660
there are receptors that
are bound to ligands.

667
00:45:10,660 --> 00:45:13,030
Signal transduction
has occurred.

668
00:45:13,030 --> 00:45:15,360
I've diagrammed it down here.

669
00:45:15,360 --> 00:45:17,620
And F-actin, these
little filaments,

670
00:45:17,620 --> 00:45:22,060
have formed in the direction
in which the cell is moving.

671
00:45:22,060 --> 00:45:26,110
And where the cell is
detaching so that the cell can

672
00:45:26,110 --> 00:45:28,720
move forwards-- you have to
lift up your foot in order

673
00:45:28,720 --> 00:45:29,500
to move forward.

674
00:45:29,500 --> 00:45:31,480
It's the same thing
with the cell--

675
00:45:31,480 --> 00:45:35,110
where the cell is moving
forward, they're no ligands.

676
00:45:35,110 --> 00:45:37,720
And there's no F-actin.

677
00:45:37,720 --> 00:45:43,120
That principle is
crucial also in changing

678
00:45:43,120 --> 00:45:44,410
cell shape and sheets.

679
00:45:44,410 --> 00:45:46,420
It's a little more complicated.

680
00:45:46,420 --> 00:45:53,650
But, again, there are receptors
that interact with Rho GPTases,

681
00:45:53,650 --> 00:45:56,560
change the cytoskeleton
and cell sheets

682
00:45:56,560 --> 00:45:59,540
and change the shape
of the cell sheets.

683
00:45:59,540 --> 00:46:02,050
And this is really the
molecular underpinning

684
00:46:02,050 --> 00:46:07,210
that will get those single cells
to form tubes and bench sheets

685
00:46:07,210 --> 00:46:10,480
and all of the materials that
are needed to build organs.

686
00:46:10,480 --> 00:46:12,660
And we'll stop there.