WEBVTT 00:00:00.090 --> 00:00:02.490 The following content is provided under a Creative 00:00:02.490 --> 00:00:04.030 Commons license. 00:00:04.030 --> 00:00:06.330 Your support will help MIT OpenCourseWare 00:00:06.330 --> 00:00:10.720 continue to offer high quality educational resources for free. 00:00:10.720 --> 00:00:13.320 To make a donation or view additional materials 00:00:13.320 --> 00:00:17.280 from hundreds of MIT courses, visit MIT OpenCourseWare 00:00:17.280 --> 00:00:18.450 at ocw.mit.edu. 00:00:26.760 --> 00:00:30.750 HAZEL SIVE: All right, moving along, 00:00:30.750 --> 00:00:32.975 I want to talk about three things today. 00:00:39.810 --> 00:00:48.340 The first is breaking symmetry in the embryo, 00:00:48.340 --> 00:00:51.380 leading to the first differences that then go on 00:00:51.380 --> 00:00:56.060 to amplify into many differences in a multicellular organism. 00:00:56.060 --> 00:01:05.120 And then I'm going to talk about organic genesis and then 00:01:05.120 --> 00:01:07.670 about morphogenesis. 00:01:07.670 --> 00:01:10.250 And we'll define these terms as we go along. 00:01:14.760 --> 00:01:19.755 Let's start with this question of breaking symmetry. 00:01:23.370 --> 00:01:28.260 And I'm going to start by going back 00:01:28.260 --> 00:01:33.390 to the last handout of last lecture 00:01:33.390 --> 00:01:35.740 that you should have looked at-- 00:01:35.740 --> 00:01:41.100 hm, I wonder if our AV expert could do something 00:01:41.100 --> 00:01:41.950 to the screen. 00:01:41.950 --> 00:01:43.320 I don't think it's the computer. 00:01:43.320 --> 00:01:44.520 I think it's the screens. 00:01:44.520 --> 00:01:45.780 Let's see if we can do this. 00:01:48.940 --> 00:01:54.790 The last handout I gave you was a consideration 00:01:54.790 --> 00:01:57.732 of how different parts of the embryo become different. 00:01:57.732 --> 00:02:00.190 And I started off-- and you might have this in front of you 00:02:00.190 --> 00:02:00.690 still-- 00:02:00.690 --> 00:02:04.000 I started off with an embryo, a fertilized egg, 00:02:04.000 --> 00:02:08.335 that's got some kind of asymmetry to it. 00:02:08.335 --> 00:02:12.320 And I've called it a determinant. 00:02:12.320 --> 00:02:15.770 And at the first cell division, look, 00:02:15.770 --> 00:02:18.710 I've put that determinant into one cell 00:02:18.710 --> 00:02:21.020 and not the other cell. 00:02:21.020 --> 00:02:24.500 One cell and not the other cell. 00:02:24.500 --> 00:02:28.040 Now, let's say that that determinant has 00:02:28.040 --> 00:02:31.370 some effect on changing the secreted factors-- 00:02:31.370 --> 00:02:33.350 oh, fantastic, thank you very much. 00:02:33.350 --> 00:02:39.970 It's like magic-- that determinant has an effect. 00:02:39.970 --> 00:02:46.090 And it actually elicits signals to be secreted from the cell. 00:02:46.090 --> 00:02:48.010 Then look what happens at the next stage, 00:02:48.010 --> 00:02:51.760 at the four cell stage, here is a cell that's 00:02:51.760 --> 00:02:53.440 secreting a signal. 00:02:53.440 --> 00:02:56.850 And it's doing something to the cell that receives the signal. 00:02:56.850 --> 00:02:58.900 It's making it brown. 00:02:58.900 --> 00:03:03.010 And that signal in turn then elicits other signals. 00:03:03.010 --> 00:03:04.990 So the brown cells start signaling 00:03:04.990 --> 00:03:06.280 to the cell next door. 00:03:06.280 --> 00:03:10.810 And as cell division precedes, you now get gray cell. 00:03:10.810 --> 00:03:13.840 And this is a theoretical, but a real, 00:03:13.840 --> 00:03:18.760 demonstration of how the embryo becomes different over time, 00:03:18.760 --> 00:03:21.250 starting with an initial asymmetry. 00:03:21.250 --> 00:03:24.550 That is then built upon due to segregation 00:03:24.550 --> 00:03:28.990 of localized factors and also due to cell-cell signaling. 00:03:28.990 --> 00:03:31.420 And all of this comes together to make 00:03:31.420 --> 00:03:34.630 these different regions, which I've cool territories, which 00:03:34.630 --> 00:03:36.460 eventually will go on to give rise 00:03:36.460 --> 00:03:40.750 to different kinds of cells or different groups of kinds 00:03:40.750 --> 00:03:43.140 of cells. 00:03:43.140 --> 00:03:45.180 If you look in a real embryo-- 00:03:45.180 --> 00:03:48.729 this is a fruit fly embryo, Drosophila embryo. 00:03:48.729 --> 00:03:49.770 You don't have a handout. 00:03:49.770 --> 00:03:51.100 Just look on the screen. 00:03:51.100 --> 00:03:53.670 You can see the sequential division. 00:03:53.670 --> 00:03:56.970 And you can see this by looking at changes in gene expression 00:03:56.970 --> 00:03:57.640 patterns. 00:03:57.640 --> 00:03:58.890 And it's really spectacular. 00:03:58.890 --> 00:04:00.320 This is a drawing. 00:04:00.320 --> 00:04:01.740 But you can actually look at this 00:04:01.740 --> 00:04:03.810 in terms of in situ hybridization, 00:04:03.810 --> 00:04:06.090 that technique I mentioned last time, 00:04:06.090 --> 00:04:09.190 where one can look at where RNAs or proteins, 00:04:09.190 --> 00:04:11.100 and in the case of in situ hybridization, 00:04:11.100 --> 00:04:14.610 it's RNA, where RNAs are localized. 00:04:14.610 --> 00:04:16.459 And in the very early embryo, there 00:04:16.459 --> 00:04:18.810 is an asymmetry of a protein called 00:04:18.810 --> 00:04:21.930 bicoid, where there's more on one side than the other. 00:04:21.930 --> 00:04:24.760 A little later, after fertilization, 00:04:24.760 --> 00:04:28.500 you start to see literally these stripes of RNA 00:04:28.500 --> 00:04:30.870 or protein across the embryo. 00:04:30.870 --> 00:04:34.080 And then the stripes of different proteins and RNA 00:04:34.080 --> 00:04:39.600 get narrower as the embryo is divided up into its segments 00:04:39.600 --> 00:04:41.440 and so on. 00:04:41.440 --> 00:04:45.460 And so what you see out of this is the embryo being divided up 00:04:45.460 --> 00:04:48.610 from one large territory into smaller and smaller 00:04:48.610 --> 00:04:49.720 territories. 00:04:49.720 --> 00:04:52.225 But the question is, where does it all start? 00:04:55.710 --> 00:05:06.210 And so the first asymmetry has got something 00:05:06.210 --> 00:05:09.770 to do with fertilization. 00:05:09.770 --> 00:05:27.130 It can either occur before, at, or after fertilization, 00:05:27.130 --> 00:05:36.010 where the haploid egg and sperm fuse to become a zygote. 00:05:36.010 --> 00:05:41.930 And somewhere in this process, this asymmetry develops. 00:05:41.930 --> 00:05:45.640 In the case of frogs, the first asymmetries 00:05:45.640 --> 00:05:49.591 are formed before fertilization, and also in Drosophila, fruit 00:05:49.591 --> 00:05:50.090 flies. 00:05:53.510 --> 00:05:58.820 In the case of Caenorhabditis, also 00:05:58.820 --> 00:06:04.430 known as the worm, asymmetry forms at fertilization. 00:06:04.430 --> 00:06:08.840 And in the case of mammals, like ourselves, the asymmetries 00:06:08.840 --> 00:06:11.010 appear to form of to fertilization. 00:06:15.390 --> 00:06:18.690 And these asymmetries eventually build up 00:06:18.690 --> 00:06:22.110 to give rise to a system of positional coordinates, 00:06:22.110 --> 00:06:25.140 kind of like the lines of latitude and longitude 00:06:25.140 --> 00:06:27.280 on the globe. 00:06:27.280 --> 00:06:47.710 And these are called the axes, which are positional values. 00:06:47.710 --> 00:06:50.020 And there are three of them. 00:06:50.020 --> 00:06:52.540 I'm just going to put the initials on the board. 00:06:52.540 --> 00:06:55.720 And then I'll show you a slide, and you can get these later. 00:06:55.720 --> 00:07:01.360 They're called a A/P, D/V, and L/R. 00:07:01.360 --> 00:07:04.450 And if you look on the screen, you'll 00:07:04.450 --> 00:07:08.230 see my diagram of a mouse, the same in ourselves, 00:07:08.230 --> 00:07:11.710 where there is this A/P coordinate, which 00:07:11.710 --> 00:07:16.420 stands for anteroposterior, where antero is the head 00:07:16.420 --> 00:07:20.950 and posterior is the tail, or as far back as your body goes. 00:07:20.950 --> 00:07:25.870 Then there's dorsal which refers to back and ventral, belly. 00:07:25.870 --> 00:07:28.330 And then there's left and right. 00:07:28.330 --> 00:07:32.290 And these values are kind of like north, 00:07:32.290 --> 00:07:35.530 south, east, west, and then degrees 00:07:35.530 --> 00:07:38.570 on either side of the meridian. 00:07:38.570 --> 00:07:40.910 They help the embryo figure out where 00:07:40.910 --> 00:07:44.030 to put different organs in different cell types. 00:07:44.030 --> 00:07:46.550 And I'm not going to dwell on them in the interest of time, 00:07:46.550 --> 00:07:48.110 but there are a whole sets of genes 00:07:48.110 --> 00:07:51.890 that are involved in setting up these coordinates. 00:07:51.890 --> 00:07:54.890 The one thing that I will dwell on more 00:07:54.890 --> 00:07:57.050 is a specific example of setting up 00:07:57.050 --> 00:08:15.210 the first asymmetry in Caenorhabditis, 00:08:15.210 --> 00:08:18.990 where this first asymmetry is set up at fertilization. 00:08:18.990 --> 00:08:21.480 And the bottom line-- we'll look on it on your hand out 00:08:21.480 --> 00:08:22.620 in a moment-- 00:08:22.620 --> 00:08:33.419 is that the sperm entry and particularly the centriole 00:08:33.419 --> 00:08:42.010 brought in by the sperm causes a massive rearrangement 00:08:42.010 --> 00:08:46.750 of the cytoskeleton in the egg or in the zygote. 00:08:46.750 --> 00:08:50.710 The cytoskeleton we mentioned way back in Lecture 2. 00:08:50.710 --> 00:08:55.930 It is the system of actin, filaments, and microtubule 00:08:55.930 --> 00:08:59.440 tubules that give the cell shape and allow it, 00:08:59.440 --> 00:09:02.890 as we'll discuss later on, to move and to help 00:09:02.890 --> 00:09:05.800 build the animal or the plant. 00:09:05.800 --> 00:09:15.050 So this the sperm entry causes cytoskeletal re-arrangement. 00:09:21.230 --> 00:09:29.730 And this particularly pertains to actin and tubulin, where 00:09:29.730 --> 00:09:36.620 the tubulin forms microtubules and the actin 00:09:36.620 --> 00:09:39.605 forms microfilaments. 00:09:46.820 --> 00:09:49.760 And with the cytoskeletal re-arrangement, 00:09:49.760 --> 00:09:53.240 a protein called Par 6, that is firmly 00:09:53.240 --> 00:09:57.170 attached to the cytoskeleton, is pulled 00:09:57.170 --> 00:10:02.200 to one side of the zygote, leaving one side of the zygote 00:10:02.200 --> 00:10:06.240 with lots of par-6 on the other side with none. 00:10:06.240 --> 00:10:10.360 And at the first cell division, one cell gets lots of Par 6, 00:10:10.360 --> 00:10:11.920 and the other gets none. 00:10:11.920 --> 00:10:14.290 And that gives you your first asymmetry 00:10:14.290 --> 00:10:16.810 upon which the embryo builds to give rise 00:10:16.810 --> 00:10:19.850 to all its different cell types and organs. 00:10:19.850 --> 00:10:25.480 So the cytoskeletal re-arrangement pulls 00:10:25.480 --> 00:10:31.708 the attached Par 6 protein-- 00:10:36.090 --> 00:10:37.960 and this is a regulatory protein. 00:10:37.960 --> 00:10:39.695 It doesn't matter exactly what it does-- 00:10:44.530 --> 00:10:54.060 to the future anterior side of the embryo. 00:10:54.060 --> 00:10:57.900 And in doing so, it actually sets up the anterior side 00:10:57.900 --> 00:10:58.860 of the embryo. 00:10:58.860 --> 00:11:02.550 Let's look at your first slide or your first handout. 00:11:06.070 --> 00:11:10.130 This is a diagram of the early worm egg, 00:11:10.130 --> 00:11:12.260 actually the very early worm zygote, 00:11:12.260 --> 00:11:16.510 because here is the egg nucleus, called a pronucleus. 00:11:16.510 --> 00:11:18.200 It's haploid. 00:11:18.200 --> 00:11:21.370 The sperm pronucleus has just entered. 00:11:21.370 --> 00:11:25.160 And the cytoskeleton I've represented by this grid. 00:11:25.160 --> 00:11:29.050 And Par 6 protein is represented by the red 00:11:29.050 --> 00:11:31.910 that you can see on the screen surrounding 00:11:31.910 --> 00:11:36.170 the outside of the zygote. 00:11:36.170 --> 00:11:41.120 Here's the sperm entry, causing cytoskeletal contraction. 00:11:41.120 --> 00:11:46.260 And with it, because par-6 is attached to the cytoskeleton, 00:11:46.260 --> 00:11:50.090 Par 6 is moved to one side of the cell. 00:11:50.090 --> 00:11:52.100 That's the most important thing. 00:11:52.100 --> 00:11:55.760 Later on, the first cell division along this 00:11:55.760 --> 00:11:57.630 dotted line here. 00:11:57.630 --> 00:12:01.040 And you can see that the first cell, in the first cell 00:12:01.040 --> 00:12:04.280 division, one of the cells would get most of the Par 6 00:12:04.280 --> 00:12:07.650 and the other cell would get very little. 00:12:07.650 --> 00:12:09.360 This is a very beautiful mechanism 00:12:09.360 --> 00:12:13.020 that's been worked out really beautifully in worms. 00:12:13.020 --> 00:12:19.190 Here's a movie that I guess isn't going to work. 00:12:19.190 --> 00:12:21.020 You know what, it was working great 00:12:21.020 --> 00:12:22.310 before I walked in this room. 00:12:22.310 --> 00:12:23.490 But it's not going to work. 00:12:23.490 --> 00:12:25.870 So I'm going to post it as a movie. 00:12:25.870 --> 00:12:28.710 And you can go to the URL and you can get it. 00:12:28.710 --> 00:12:30.590 And you'll see what this movie does 00:12:30.590 --> 00:12:33.680 will show you fluorescently labeled Par protein. 00:12:33.680 --> 00:12:36.350 It's actually a different protein than Par 6. 00:12:36.350 --> 00:12:38.900 And you'll be able to see it moving beautifully 00:12:38.900 --> 00:12:41.350 to one side of the embryo and not the other. 00:12:51.570 --> 00:12:56.410 Number 2, organogenesis. 00:13:08.940 --> 00:13:14.060 An organ, as I've written on the screen, 00:13:14.060 --> 00:13:17.570 is a functional unit of many cell types 00:13:17.570 --> 00:13:22.490 that are arranged obligatorily in 00:13:22.490 --> 00:13:24.710 a three-dimensional structure that allows 00:13:24.710 --> 00:13:27.260 them to function together. 00:13:27.260 --> 00:13:32.900 So the problem we have here is that an organ is many cell 00:13:32.900 --> 00:13:46.940 types, arranged in 3-D, such that there 00:13:46.940 --> 00:13:51.830 is a specific functional outcome, 00:13:51.830 --> 00:13:55.940 like the heart pumps blood, the kidney filters blood, 00:13:55.940 --> 00:13:58.280 the eyes see. 00:13:58.280 --> 00:14:02.360 All of these things require both of these correct cell 00:14:02.360 --> 00:14:04.670 types and 3-D organization. 00:14:04.670 --> 00:14:08.600 And just this sentence or just this phrase 00:14:08.600 --> 00:14:12.350 raises two questions. 00:14:12.350 --> 00:14:15.200 How do you get all the cell types to the correct place? 00:14:32.130 --> 00:14:34.200 And how are they put into the correct structure? 00:14:56.180 --> 00:15:00.080 Let's phrase the problem by looking at the kidney. 00:15:00.080 --> 00:15:05.690 The kidney is one of the most complex organs. 00:15:05.690 --> 00:15:07.050 It does two things. 00:15:07.050 --> 00:15:10.400 It filters the blood and gets waste products out 00:15:10.400 --> 00:15:12.860 of the blood, particularly products 00:15:12.860 --> 00:15:15.810 of amino acid metabolism. 00:15:15.810 --> 00:15:18.830 And it also maintains water balance. 00:15:18.830 --> 00:15:20.780 Both of those things are crucial functions 00:15:20.780 --> 00:15:25.220 of that kidney, which consists of about 15 different cell 00:15:25.220 --> 00:15:29.210 types, which are connected into several types of tubes 00:15:29.210 --> 00:15:32.010 that lead on fluidly from one to the next. 00:15:32.010 --> 00:15:34.730 You have one type of tube that does one thing. 00:15:34.730 --> 00:15:36.560 It's connected to the next tube, which 00:15:36.560 --> 00:15:40.220 does the next thing, connected to the next tube and so on. 00:15:40.220 --> 00:15:42.020 The tubes are very long. 00:15:42.020 --> 00:15:44.120 They form a 3-D organization. 00:15:44.120 --> 00:15:46.760 And they form filtration units, called nephrons. 00:15:46.760 --> 00:15:48.890 Here are part of the nephrons. 00:15:48.890 --> 00:15:51.860 And you just have to look at this without any knowledge 00:15:51.860 --> 00:15:54.080 to see that this is a complex structure. 00:15:57.150 --> 00:16:01.120 This is a distant view, so you can't see the cells here. 00:16:01.120 --> 00:16:03.450 Low magnification structure. 00:16:03.450 --> 00:16:05.460 This is a really complex organ. 00:16:05.460 --> 00:16:09.810 And it takes a moment's thought to wonder how something 00:16:09.810 --> 00:16:11.830 like this gets put together. 00:16:11.830 --> 00:16:14.360 And, of course, this is not only important for developments. 00:16:14.360 --> 00:16:17.160 It's important for thinking about how you would replace 00:16:17.160 --> 00:16:20.510 someone's kidney with something that was artificial, 00:16:20.510 --> 00:16:24.130 and not just using donated organs. 00:16:24.130 --> 00:16:26.460 Could you build something like a kidney 00:16:26.460 --> 00:16:30.640 and use it in place of donated organs? 00:16:30.640 --> 00:16:33.960 So the question of organogenesis is of huge importance 00:16:33.960 --> 00:16:38.130 both to basic researches, to physicians trying 00:16:38.130 --> 00:16:41.100 to understand what goes wrong when organs fail, 00:16:41.100 --> 00:16:44.310 and to bioengineers who are trying to build organs that 00:16:44.310 --> 00:16:45.660 would replace human versions. 00:16:49.080 --> 00:16:51.510 Let's start by tackling the first question. 00:16:51.510 --> 00:16:56.520 How do you put different cell types in the correct place? 00:16:56.520 --> 00:16:58.860 And there are three possibilities, all of which 00:16:58.860 --> 00:17:00.080 are used by the body. 00:17:19.790 --> 00:17:23.460 OK, so one, they can move there. 00:17:23.460 --> 00:17:26.500 There can be all these cell types all over the body. 00:17:26.500 --> 00:17:29.490 And they can say, oh, OK, we need to go move over here 00:17:29.490 --> 00:17:31.630 to build a kidney. 00:17:31.630 --> 00:17:34.780 OK, it seems unlikely, but in fact, it's true. 00:17:34.780 --> 00:17:40.240 And that process would be migration, 00:17:40.240 --> 00:17:43.090 where the cells come from all over the place 00:17:43.090 --> 00:17:44.800 to build the organ. 00:17:44.800 --> 00:17:46.645 The cells need to know where to go. 00:17:53.850 --> 00:17:57.090 And that just pushes the problem back one. 00:17:57.090 --> 00:18:01.650 But the great example of cell migration is the limb. 00:18:01.650 --> 00:18:04.500 Most of the cells in your limbs and mine 00:18:04.500 --> 00:18:07.800 did not come right from where the limb grew. 00:18:07.800 --> 00:18:10.380 They migrated there from the spinal cord. 00:18:10.380 --> 00:18:12.360 They migrated there from the muscles 00:18:12.360 --> 00:18:14.880 on the sides of the body. 00:18:14.880 --> 00:18:18.360 And the blood vessels also grew in from the cells 00:18:18.360 --> 00:18:20.450 that were distant. 00:18:20.450 --> 00:18:28.030 So the limb puts it all together by moving cells around. 00:18:28.030 --> 00:18:30.480 How else could you get cells to the right place? 00:18:37.730 --> 00:18:38.710 See, it's not so easy. 00:18:38.710 --> 00:18:40.710 OK, so here's another one. 00:18:40.710 --> 00:18:45.240 Well, you could in one place tell a bunch of different cells 00:18:45.240 --> 00:18:47.710 to form at the same time. 00:18:47.710 --> 00:18:50.080 You could have your organ and say, all right, 00:18:50.080 --> 00:18:53.790 we need cell types 1 to 10. 00:18:53.790 --> 00:18:54.710 Form. 00:18:54.710 --> 00:18:55.780 Here's some signals. 00:18:55.780 --> 00:18:57.730 You will form in this one place. 00:18:57.730 --> 00:18:59.620 And in fact that happens. 00:18:59.620 --> 00:19:06.340 This is called co-induction, where 00:19:06.340 --> 00:19:17.040 many cell types or several cell types form in one place, 00:19:17.040 --> 00:19:23.550 often because one signal can act at different concentrations 00:19:23.550 --> 00:19:26.010 to give rise to different cell types. 00:19:26.010 --> 00:19:28.980 So many cell types form in one place, 00:19:28.980 --> 00:19:37.980 often due to a concentration gradient of an inducer, 00:19:37.980 --> 00:19:38.505 of a signal. 00:19:48.300 --> 00:19:56.400 And the great example of this is the spinal cord, and the nerves 00:19:56.400 --> 00:20:01.260 in the spinal cord, which arise by co-induction of actually 00:20:01.260 --> 00:20:05.060 about two different inducers. 00:20:05.060 --> 00:20:10.580 And the third one is called sequential induction. 00:20:10.580 --> 00:20:19.540 And this is how the kidneys forms, 00:20:19.540 --> 00:20:22.180 where the idea with sequential induction 00:20:22.180 --> 00:20:24.760 is that a cell type forms. 00:20:24.760 --> 00:20:28.780 And it says, OK, I need this other cell type to work with. 00:20:28.780 --> 00:20:30.670 And it instructs the cells around 00:20:30.670 --> 00:20:32.680 to become another cell type. 00:20:32.680 --> 00:20:35.890 And those cells in turn might instruct some cells around them 00:20:35.890 --> 00:20:37.690 to become another cell type. 00:20:37.690 --> 00:20:39.370 And there's this conversation going 00:20:39.370 --> 00:20:43.870 on sequentially in the place where the organ will form. 00:20:43.870 --> 00:20:56.590 So cell type 1 induces or signals 00:20:56.590 --> 00:21:07.390 to type 2, which induces type 3, etc. 00:21:07.390 --> 00:21:12.730 And a great example of this is the kidney, 00:21:12.730 --> 00:21:17.470 where I will say it is still not known how you build a kidney. 00:21:17.470 --> 00:21:18.970 Some of the steps are understood. 00:21:18.970 --> 00:21:20.920 But there's no organ where we can 00:21:20.920 --> 00:21:23.080 say these are all the steps that build the organ. 00:21:23.080 --> 00:21:24.160 It's incredibly complex. 00:21:27.910 --> 00:21:30.460 Good. 00:21:30.460 --> 00:21:33.340 That's all I'm going to say about organogenesis, to throw 00:21:33.340 --> 00:21:35.860 out at your this complex problem. 00:21:35.860 --> 00:21:38.920 And you can explore it more in later courses. 00:21:38.920 --> 00:21:42.460 I am going to talk more, though, about this question of 3D 00:21:42.460 --> 00:21:43.150 structure. 00:21:48.420 --> 00:21:50.772 And that is the question of morphogenesis. 00:21:59.780 --> 00:22:02.740 Oranogenesis, morphogenesis, you might 00:22:02.740 --> 00:22:06.220 have heard of histogenesis, which means building tissues. 00:22:06.220 --> 00:22:09.160 The genesis part refers to building. 00:22:09.160 --> 00:22:12.700 That's what it means, building of something. 00:22:12.700 --> 00:22:21.040 Morphogenesis, building a three-dimensional structure, 00:22:21.040 --> 00:22:31.570 or the generation of form is what you'll see. 00:22:31.570 --> 00:22:37.320 And what that really means is building 3D structure. 00:22:44.510 --> 00:22:46.880 And this relates to organogenesis 00:22:46.880 --> 00:22:49.400 because in organogenesis one of the things that's 00:22:49.400 --> 00:22:52.670 hidden on the board above was the question 00:22:52.670 --> 00:23:01.453 of getting cells of an organ into the correct 3D structure. 00:23:12.810 --> 00:23:16.380 And, of course, this question of 3D structure 00:23:16.380 --> 00:23:18.930 is intuitively quite clear. 00:23:18.930 --> 00:23:22.740 You can imagine a human heart or having 00:23:22.740 --> 00:23:25.260 some kind of animal's heart in front of you. 00:23:25.260 --> 00:23:27.210 It's an extraordinary structure. 00:23:27.210 --> 00:23:29.930 It's actually a folded tube, where the walls of the tube 00:23:29.930 --> 00:23:31.780 have become very muscular. 00:23:31.780 --> 00:23:35.100 And the heart will pump with great regularity. 00:23:35.100 --> 00:23:38.700 It's a controlled pump that can speed up or slow down depending 00:23:38.700 --> 00:23:42.320 on the how the animal is doing. 00:23:42.320 --> 00:23:47.240 And that heart contains about 10 different kinds of cells. 00:23:47.240 --> 00:23:49.940 And you can imagine having one in front of you. 00:23:49.940 --> 00:23:51.860 And you can imagine my coming along 00:23:51.860 --> 00:23:54.890 with some kind of protease or calcium 00:23:54.890 --> 00:23:58.010 free medium that will cause the cells of the heart 00:23:58.010 --> 00:24:02.490 to leave one another, deconstruct 00:24:02.490 --> 00:24:03.760 the structure of the heart. 00:24:03.760 --> 00:24:06.510 Now you've got a heart that's not this pump looking 00:24:06.510 --> 00:24:07.920 tube structure. 00:24:07.920 --> 00:24:09.840 It's a pile of cells. 00:24:09.840 --> 00:24:13.552 The same cells that were in the organ of the heart, but, 00:24:13.552 --> 00:24:14.510 of course, they're not. 00:24:14.510 --> 00:24:16.110 They're just a pile of cells. 00:24:16.110 --> 00:24:16.950 They're all there. 00:24:16.950 --> 00:24:18.780 They might all be alive. 00:24:18.780 --> 00:24:20.370 But they're not acting. 00:24:20.370 --> 00:24:22.780 And that's really an engineering problem, 00:24:22.780 --> 00:24:24.790 which is what morphogenesis is all about. 00:24:24.790 --> 00:24:27.390 And I want to just discuss morphogenesis with you 00:24:27.390 --> 00:24:33.180 because I think as a science and engineering problem, 00:24:33.180 --> 00:24:36.100 it's really an extraordinary one to think about. 00:24:36.100 --> 00:24:38.880 And it's extraordinary to think about because really there's 00:24:38.880 --> 00:24:41.550 only one building material by which all 00:24:41.550 --> 00:24:46.440 the structures of all organisms are built. And that's cells. 00:24:46.440 --> 00:24:49.650 You can't find different plastics or different metals 00:24:49.650 --> 00:24:52.410 or different alloys to build things with, 00:24:52.410 --> 00:24:54.420 it's just one building material. 00:24:54.420 --> 00:24:56.940 And it's really amazing what life 00:24:56.940 --> 00:24:59.130 has managed to do with cells. 00:24:59.130 --> 00:25:02.290 And that's what we'll explore for the rest of the lecture. 00:25:02.290 --> 00:25:06.540 So getting cells in organs into the correct 3D structure. 00:25:09.900 --> 00:25:16.500 This is a great example of 3D structure, another one, 00:25:16.500 --> 00:25:21.540 the lungs, which are about a 20-fold iteration of branching. 00:25:21.540 --> 00:25:25.470 You start off with one tube, the trachea, which 00:25:25.470 --> 00:25:28.200 branches into the two bronchi. 00:25:28.200 --> 00:25:31.470 And those branch and they branch and they branch. 00:25:31.470 --> 00:25:33.900 It's about a 20-fold branching. 00:25:33.900 --> 00:25:37.020 And you end up with many, many little tubes. 00:25:37.020 --> 00:25:39.850 In this rendition, the ends of the tubes, 00:25:39.850 --> 00:25:42.660 which are sacs of cells, have been taken away. 00:25:42.660 --> 00:25:45.870 But it's through these tubes that oxygen moves or air moves. 00:25:45.870 --> 00:25:49.140 The oxygen is extracted from the air, moves 00:25:49.140 --> 00:25:54.090 into the bloodstream, and then the waste air is exhaled. 00:25:54.090 --> 00:25:55.530 And the same thing starts again. 00:25:55.530 --> 00:25:59.190 How do you build these lungs with this branching arrangement 00:25:59.190 --> 00:25:59.774 of cells? 00:25:59.774 --> 00:26:01.440 And indeed, how do you build the kidney? 00:26:06.210 --> 00:26:10.910 You know, the problem really phrases like this-- 00:26:10.910 --> 00:26:15.290 and if we had more time today, I would sit and challenge you 00:26:15.290 --> 00:26:17.630 for five or 10 minutes to go and think 00:26:17.630 --> 00:26:21.800 about how you take a pile of cells from the early embryo 00:26:21.800 --> 00:26:23.660 and build that structure, which could 00:26:23.660 --> 00:26:26.150 be what it is or could be something 00:26:26.150 --> 00:26:28.450 that represents an organ. 00:26:28.450 --> 00:26:30.370 And while I'm moving the boards, you 00:26:30.370 --> 00:26:33.520 can think about how you would take those cells 00:26:33.520 --> 00:26:35.830 and turn them into a 3D structure. 00:26:35.830 --> 00:26:38.571 And we'll see if we have concordance in our thinking 00:26:38.571 --> 00:26:39.070 here. 00:26:53.000 --> 00:26:55.400 All right, so let's turn this pile of cells 00:26:55.400 --> 00:26:57.140 into a 3D structure. 00:26:57.140 --> 00:26:58.940 And let's pull out some processes 00:26:58.940 --> 00:27:02.570 that we can talk about in lay terms, no scientific terms. 00:27:02.570 --> 00:27:04.370 And then I'll put some molecular labels 00:27:04.370 --> 00:27:07.880 on that will help you understand what we're talking about. 00:27:07.880 --> 00:27:11.450 And process indeed has two s's. 00:27:11.450 --> 00:27:13.990 There we go. 00:27:13.990 --> 00:27:16.160 Well, one thing you know if you look 00:27:16.160 --> 00:27:19.040 at my pile of cells in the 3D structure 00:27:19.040 --> 00:27:22.160 is that those cells have been sorted out. 00:27:22.160 --> 00:27:23.810 I've put them in different colors, 00:27:23.810 --> 00:27:26.240 in groups of different colors. 00:27:26.240 --> 00:27:29.530 So I'm going to write that the cells sort out. 00:27:33.620 --> 00:27:36.470 And there is a molecular basis for that. 00:27:36.470 --> 00:27:39.370 It's called homotypic adhesion, where 00:27:39.370 --> 00:27:41.960 like cells tend to bind to one another, 00:27:41.960 --> 00:27:43.655 so that they can function as a unit. 00:27:52.470 --> 00:27:57.240 But, of course, in order to get the cells to sort out, 00:27:57.240 --> 00:28:00.130 they actually had to move. 00:28:00.130 --> 00:28:02.260 Yes? 00:28:02.260 --> 00:28:04.015 Say, yes. 00:28:04.015 --> 00:28:04.515 OK. 00:28:08.220 --> 00:28:11.550 And they moved because of their cytoskeleton, 00:28:11.550 --> 00:28:14.550 which was rearranging and changing and allowing 00:28:14.550 --> 00:28:15.760 them to do so. 00:28:15.760 --> 00:28:18.390 So the molecular basis for movement 00:28:18.390 --> 00:28:26.430 is cytoskeletal change or rearrangement. 00:28:26.430 --> 00:28:28.680 What else is on my list? 00:28:28.680 --> 00:28:32.300 You know, the pile of cells that I've got there, 00:28:32.300 --> 00:28:34.380 it's meant to look loose, like it 00:28:34.380 --> 00:28:36.240 would be a pile of cells that would just 00:28:36.240 --> 00:28:39.840 spread out all over the table if I dumped it out. 00:28:39.840 --> 00:28:43.650 But the organ that I drew is meant to look tight. 00:28:43.650 --> 00:28:45.990 Those cells are stuck together. 00:28:45.990 --> 00:28:48.100 And that is one of the things that happens. 00:28:48.100 --> 00:28:50.295 The cells stick together. 00:28:53.560 --> 00:28:59.130 And they do so because of cellular junctions, which 00:28:59.130 --> 00:29:01.920 are particular collections of proteins 00:29:01.920 --> 00:29:03.940 that cause cells to stick together, 00:29:03.940 --> 00:29:07.920 often in a really waterproof kind of a way. 00:29:07.920 --> 00:29:09.300 The cells change shape. 00:29:09.300 --> 00:29:12.120 They've gone from balls to triangles to columns. 00:29:18.400 --> 00:29:22.135 And that is also driven by cytoskeletal changes. 00:29:30.980 --> 00:29:33.500 And then the two lost processes on my list 00:29:33.500 --> 00:29:35.360 I'm not going to explore more because we 00:29:35.360 --> 00:29:37.180 had a whole lecture on them. 00:29:37.180 --> 00:29:39.350 Cells can divide, and they can die. 00:29:39.350 --> 00:29:41.210 You can get rid of the excess cells. 00:29:41.210 --> 00:29:43.040 And you can generate more cells to build 00:29:43.040 --> 00:29:52.130 your organ by the processes of cell division and cell death. 00:29:52.130 --> 00:29:54.440 And we've had those before, so we aren't going 00:29:54.440 --> 00:29:56.850 to talk about those again. 00:29:56.850 --> 00:30:03.380 But I will just put up cell cycle control and apoptosis. 00:30:08.140 --> 00:30:08.640 Good. 00:30:14.592 --> 00:30:17.324 I-- yes? 00:30:17.324 --> 00:30:21.752 STUDENT: What about the [INAUDIBLE] the organ, 00:30:21.752 --> 00:30:26.690 [INAUDIBLE] 00:30:26.690 --> 00:30:28.890 HAZEL SIVE: Ah, great question. 00:30:28.890 --> 00:30:31.970 The question is, how do the cells know where to go? 00:30:31.970 --> 00:30:34.340 How do they know that the dark blue ones 00:30:34.340 --> 00:30:37.670 are on the left and the columna brown ones are on the right? 00:30:37.670 --> 00:30:38.990 It's a great question. 00:30:38.990 --> 00:30:41.070 And you know, if we had more time, 00:30:41.070 --> 00:30:42.620 I think that the thing would come up 00:30:42.620 --> 00:30:45.621 with was the notion of some kind of plan, 00:30:45.621 --> 00:30:47.870 that there are instructions somewhere that are telling 00:30:47.870 --> 00:30:49.460 the cells where to go. 00:30:49.460 --> 00:30:50.990 What are those instructions? 00:30:50.990 --> 00:30:53.660 Well, they're somehow in the genes. 00:30:53.660 --> 00:30:55.910 But it's more than that. 00:30:55.910 --> 00:30:57.680 I don't think that there is actually 00:30:57.680 --> 00:31:00.170 a set of instructions in the genes 00:31:00.170 --> 00:31:03.930 that says build this organ or the kidney or anything else. 00:31:03.930 --> 00:31:08.030 There's a set of instructions that unfolds 00:31:08.030 --> 00:31:10.110 as the organ is being built. 00:31:10.110 --> 00:31:12.740 And I think what's in the genes are the first steps 00:31:12.740 --> 00:31:14.390 of those instructions. 00:31:14.390 --> 00:31:17.180 And then they kind of unfold bit by bit. 00:31:17.180 --> 00:31:19.250 So the outcome is the organ. 00:31:19.250 --> 00:31:21.770 And there is some kind of a plan. 00:31:21.770 --> 00:31:25.760 But we don't have any evidence that there's any kind of plan 00:31:25.760 --> 00:31:27.980 actually written in the genes. 00:31:27.980 --> 00:31:29.730 OK, it's a fascinating question. 00:31:29.730 --> 00:31:30.230 Good. 00:31:33.210 --> 00:31:35.700 Back to the toolkit. 00:31:35.700 --> 00:31:39.900 This toolkit to build all organs of cells. 00:31:52.020 --> 00:31:54.210 But cells, you know, are not just 00:31:54.210 --> 00:31:57.000 equivalent to bricks one shape. 00:31:57.000 --> 00:31:58.500 They can actually change. 00:31:58.500 --> 00:32:00.910 So it's not quite fair that I said to you 00:32:00.910 --> 00:32:02.460 this is different than engineering 00:32:02.460 --> 00:32:04.440 where you've only got one material. 00:32:04.440 --> 00:32:06.850 It's true you've only got one material. 00:32:06.850 --> 00:32:07.860 But it can change. 00:32:07.860 --> 00:32:11.130 It can change its shape, and it can move around. 00:32:11.130 --> 00:32:14.640 And the two kinds of things you really need to know 00:32:14.640 --> 00:32:21.935 are involved are single cells and cell sheets. 00:32:26.240 --> 00:32:29.905 And single cells and cell sheets are interchangeable from one 00:32:29.905 --> 00:32:30.405 another. 00:32:33.180 --> 00:32:35.875 Single cells are also called mesenchyme. 00:32:40.400 --> 00:32:42.320 [INAUDIBLE] [? they ?] are. 00:32:42.320 --> 00:32:43.190 Single cell. 00:32:47.020 --> 00:32:52.920 And groups of mesenchymal cells can associate 00:32:52.920 --> 00:32:55.215 to become sheets of cells. 00:33:00.840 --> 00:33:04.590 And these sheets are called epithelia, 00:33:04.590 --> 00:33:06.480 or singular is epithelium. 00:33:09.970 --> 00:33:13.570 Single cells migrate. 00:33:13.570 --> 00:33:14.095 They move. 00:33:17.780 --> 00:33:20.600 And there are no junctions between the cells that 00:33:20.600 --> 00:33:23.930 allows them to be single cells. 00:33:23.930 --> 00:33:27.650 Epithelia, cell sheets, can change shape. 00:33:27.650 --> 00:33:30.890 But they don't move around that much. 00:33:30.890 --> 00:33:38.570 So they change shape as sheets. 00:33:41.720 --> 00:33:47.115 And what that allows them to do is to form coverings and tubes. 00:33:55.410 --> 00:33:58.110 I should say one very important thing. 00:33:58.110 --> 00:34:00.330 The process is reversible. 00:34:00.330 --> 00:34:04.050 If you look at the next handout, there is more information 00:34:04.050 --> 00:34:05.414 that you'll get. 00:34:12.239 --> 00:34:14.530 Here's your epithelial sheet. 00:34:14.530 --> 00:34:16.320 It's joined together by junctions. 00:34:16.320 --> 00:34:19.020 Let me make a note that there are 00:34:19.020 --> 00:34:21.690 junctions between the cells. 00:34:21.690 --> 00:34:25.093 That's what sticks the cells together is a sheet. 00:34:25.093 --> 00:34:26.469 Here are the junctions. 00:34:26.469 --> 00:34:28.020 There are two kind. 00:34:28.020 --> 00:34:30.420 There's top ones called tight junctions, 00:34:30.420 --> 00:34:32.014 which are waterproof junctions. 00:34:32.014 --> 00:34:33.389 And then they these are the ones, 00:34:33.389 --> 00:34:35.535 called adhesion junctions, which aren't so strong. 00:34:38.340 --> 00:34:44.100 Both epithelia and mesenchyme sit on the extracellular 00:34:44.100 --> 00:34:48.900 matrix, or ECM, which we mentioned way back, 00:34:48.900 --> 00:34:53.340 glycoproteins that are involved in giving support and also 00:34:53.340 --> 00:34:56.800 carrying signaling molecules to cells. 00:34:56.800 --> 00:35:00.840 And here is the conversion of the sheet to the single cells, 00:35:00.840 --> 00:35:03.480 and the single cells back to the sheet. 00:35:03.480 --> 00:35:07.950 This process of epithelial mesenchymal transition 00:35:07.950 --> 00:35:10.920 or mesenchymal epithelial transition 00:35:10.920 --> 00:35:13.260 is very important in cancer. 00:35:13.260 --> 00:35:15.480 Tumors usually start off as epithelia. 00:35:15.480 --> 00:35:18.030 The And they become metastatic. 00:35:18.030 --> 00:35:20.140 They disperse throughout the body 00:35:20.140 --> 00:35:22.290 when they become mesenchymal, or when they give off 00:35:22.290 --> 00:35:25.230 single cells, which can migrate and establish 00:35:25.230 --> 00:35:26.430 the tumor somewhere else. 00:35:26.430 --> 00:35:30.120 So this process is crucial both in building organs 00:35:30.120 --> 00:35:32.700 and in cancer biology. 00:35:32.700 --> 00:35:34.410 The other thing that you should note-- 00:35:34.410 --> 00:35:36.510 we're not going to dwell on it very much-- 00:35:36.510 --> 00:35:40.500 is that the cells in a sheet have got orientation. 00:35:40.500 --> 00:35:43.590 They've got an axis of asymmetry along one side, 00:35:43.590 --> 00:35:47.730 call the apical basal axis and an axis of asymmetry 00:35:47.730 --> 00:35:50.550 along the top, called the planar axis. 00:35:50.550 --> 00:35:53.900 But we're not going to dwell on that very much. 00:35:53.900 --> 00:36:03.950 All right, let's look what epithelial sheets 00:36:03.950 --> 00:36:06.390 do in a little more detail. 00:36:06.390 --> 00:36:18.420 So epithelial sheets or epithelial form waterproof 00:36:18.420 --> 00:36:20.070 coverings, as I've noted. 00:36:24.960 --> 00:36:30.210 And through cell shape changes, they'll also bend a cell sheet 00:36:30.210 --> 00:36:31.710 or turn it into a tube. 00:36:44.320 --> 00:36:48.460 And they do this by a series of stereotypical changes, 00:36:48.460 --> 00:37:01.220 where cells can change shape, so that kind of a square cell 00:37:01.220 --> 00:37:09.410 can become an elongated cell in one direction or a cell that's 00:37:09.410 --> 00:37:12.320 elongated in a different direction. 00:37:12.320 --> 00:37:19.230 Or it can become a wedge shaped cell. 00:37:19.230 --> 00:37:21.720 And the names of these different kinds of cells 00:37:21.720 --> 00:37:23.130 don't really matter. 00:37:23.130 --> 00:37:24.330 And they're not sequential. 00:37:24.330 --> 00:37:28.080 So this cell can become this cell. 00:37:28.080 --> 00:37:34.240 It can also become this wedge shaped cell in one fell swoop. 00:37:34.240 --> 00:37:37.500 But if you think about it, these changes in cell shape 00:37:37.500 --> 00:37:38.950 can do lots of things. 00:37:38.950 --> 00:37:42.462 For example, if cells get long and thin, 00:37:42.462 --> 00:37:45.630 then the cell sheet will lengthen. 00:37:45.630 --> 00:37:48.390 If cells get wedge shaped, and you've got a whole bunch 00:37:48.390 --> 00:37:51.240 of them getting wedge shaped-- you can draw this out-- 00:37:51.240 --> 00:37:53.820 you'll actually bend the cell sheet. 00:37:53.820 --> 00:37:54.450 Draw it out. 00:37:54.450 --> 00:37:56.721 Put a whole bunch of wedge shaped cells next to one 00:37:56.721 --> 00:37:57.220 another. 00:37:57.220 --> 00:38:00.180 And you'll see there's no way you can get a flat sheet. 00:38:00.180 --> 00:38:02.400 The cell sheet bends. 00:38:02.400 --> 00:38:04.500 And that is one of the things which 00:38:04.500 --> 00:38:07.630 drives building the structure of organs. 00:38:15.100 --> 00:38:17.860 There are a lot of different ways to make tubes. 00:38:17.860 --> 00:38:19.970 I've diagrammed them on the next few slides. 00:38:19.970 --> 00:38:21.220 You don't have these. 00:38:21.220 --> 00:38:24.280 Cell sheets can roll up to form a tube. 00:38:24.280 --> 00:38:27.670 Mesenchymal cells can condense, can come together, 00:38:27.670 --> 00:38:29.580 to form a tube. 00:38:29.580 --> 00:38:31.810 And here's a really extraordinary one. 00:38:31.810 --> 00:38:33.880 Single cells can form tubes. 00:38:33.880 --> 00:38:37.300 Tiny, single cells with a 10 micron diameter 00:38:37.300 --> 00:38:39.960 can roll up on their cell themselves 00:38:39.960 --> 00:38:42.250 or actually hollow out their middles 00:38:42.250 --> 00:38:44.050 to become tiny, tiny tubes. 00:38:50.400 --> 00:38:53.070 What about single cells? 00:38:53.070 --> 00:38:55.380 Single cells move. 00:38:55.380 --> 00:38:59.540 And this allows things to sort out 00:38:59.540 --> 00:39:02.720 and cells to get to where they need to go. 00:39:02.720 --> 00:39:04.970 But we're also going to use this property 00:39:04.970 --> 00:39:07.790 to understand the molecular principles that 00:39:07.790 --> 00:39:09.590 underlies cell shape change. 00:39:09.590 --> 00:39:11.100 And that you should know. 00:39:11.100 --> 00:39:20.220 Let's make a note that single cells move 00:39:20.220 --> 00:39:33.520 and that this allows cells to sort and tissues and organs 00:39:33.520 --> 00:39:34.180 to form. 00:39:38.050 --> 00:39:40.615 And then what I'm going to tell you over the next few slides 00:39:40.615 --> 00:39:44.920 and on your handouts is that all of the movement and all 00:39:44.920 --> 00:39:48.130 of these shape changes that I drew on the board 00:39:48.130 --> 00:39:52.330 have got to do with changing the cytoskeleton of the cell. 00:39:52.330 --> 00:39:55.090 But what I'll tell you is that it's 00:39:55.090 --> 00:39:58.450 about locally changing the cytoskeleton, 00:39:58.450 --> 00:40:01.300 where you have to stop viewing the cell as something 00:40:01.300 --> 00:40:04.540 huge, where independent things can happen 00:40:04.540 --> 00:40:06.610 in different parts of the cell. 00:40:06.610 --> 00:40:10.270 And those independent changes in the structure, 00:40:10.270 --> 00:40:13.150 in the skeleton of the cell will get the cell 00:40:13.150 --> 00:40:19.880 to become long or squat or wedge shaped or moved. 00:40:19.880 --> 00:40:30.800 So shape and movement of both sheets and single cells 00:40:30.800 --> 00:40:37.050 is controlled by changing the cytoskeleton. 00:40:46.150 --> 00:40:53.620 But it's done so locally, which means in one part of the cell. 00:40:58.030 --> 00:41:03.010 And a most important change that occurs as the cytoskeleton 00:41:03.010 --> 00:41:06.400 changes or with cytoskeletal changes or is cytoskeletal 00:41:06.400 --> 00:41:16.130 change is a polymerization of actin from G-actin, 00:41:16.130 --> 00:41:26.120 which is unpolymerized, to F-actin-- 00:41:26.120 --> 00:41:28.610 and this is reversible-- 00:41:28.610 --> 00:41:33.530 which is polymerized, non-covalently. 00:41:33.530 --> 00:41:39.590 And this F-actin will stretch the cell 00:41:39.590 --> 00:41:41.900 and help the cell to move. 00:41:41.900 --> 00:41:45.200 And let's explore that in this movie 00:41:45.200 --> 00:41:47.330 and in the rest of your handouts. 00:41:47.330 --> 00:41:51.530 This is a movie of a cell, where the actin has 00:41:51.530 --> 00:41:54.650 been labeled fluorescently. 00:41:54.650 --> 00:41:57.470 And what you can see as the cell is moving 00:41:57.470 --> 00:42:01.080 are these little filaments of bright green. 00:42:01.080 --> 00:42:04.050 Those are the polymerized F-actin. 00:42:04.050 --> 00:42:07.620 And you can see if you just focus on one, over the course 00:42:07.620 --> 00:42:10.920 of minutes, it goes away. 00:42:10.920 --> 00:42:12.960 And new ones form. 00:42:12.960 --> 00:42:15.960 And the new ones are forming in the direction 00:42:15.960 --> 00:42:18.330 that the cell is moving. 00:42:18.330 --> 00:42:21.850 And this movie really illustrates the principles 00:42:21.850 --> 00:42:26.760 underlying how the cytoskeleton is controlled. 00:42:26.760 --> 00:42:28.410 Let's draw something on the board 00:42:28.410 --> 00:42:30.600 or let's write a few things on the board 00:42:30.600 --> 00:42:33.330 and then look at your last two handouts. 00:42:33.330 --> 00:42:37.120 And what you'll understand is that the principles governing 00:42:37.120 --> 00:42:41.890 actin polymerization are really the same for both single cells 00:42:41.890 --> 00:42:44.450 and for cell sheets. 00:42:44.450 --> 00:42:59.710 The idea here is that the extracellular matrix, the ECM, 00:42:59.710 --> 00:43:16.245 connects to the plasma membrane via receptors on the plasma 00:43:16.245 --> 00:43:16.745 membrane. 00:43:23.510 --> 00:43:26.150 When ligands bind these receptors, 00:43:26.150 --> 00:43:27.710 you know what happens now. 00:43:27.710 --> 00:43:30.150 Signal transduction is activated. 00:43:33.680 --> 00:43:37.880 So the ligands plus the receptors-- 00:43:42.700 --> 00:43:46.690 and there are many different signaling pathways 00:43:46.690 --> 00:43:49.270 that can be involved-- 00:43:49.270 --> 00:43:53.170 go and activate a cascade of things, 00:43:53.170 --> 00:44:10.070 which involve kinases, a signal cascade via kinases 00:44:10.070 --> 00:44:12.980 and via special GTPase. 00:44:12.980 --> 00:44:18.095 Remember Ras was a GTPase, but this one is called Rho. 00:44:26.770 --> 00:44:33.540 And Rho GPTase it's critical in telling G-actin 00:44:33.540 --> 00:44:36.920 to polymerize and form F-actin. 00:44:36.920 --> 00:44:41.710 And so out of this the Rho GPTase 00:44:41.710 --> 00:44:47.510 tells G-actin to form F actin. 00:44:47.510 --> 00:44:50.370 And with that, various things happen. 00:44:50.370 --> 00:44:57.440 So let's look at your last handouts. 00:44:57.440 --> 00:45:00.250 Here's the cell migrating. 00:45:00.250 --> 00:45:02.590 And the thing that I want you to see 00:45:02.590 --> 00:45:05.990 is that in the direction of migration, 00:45:05.990 --> 00:45:10.660 there are receptors that are bound to ligands. 00:45:10.660 --> 00:45:13.030 Signal transduction has occurred. 00:45:13.030 --> 00:45:15.360 I've diagrammed it down here. 00:45:15.360 --> 00:45:17.620 And F-actin, these little filaments, 00:45:17.620 --> 00:45:22.060 have formed in the direction in which the cell is moving. 00:45:22.060 --> 00:45:26.110 And where the cell is detaching so that the cell can 00:45:26.110 --> 00:45:28.720 move forwards-- you have to lift up your foot in order 00:45:28.720 --> 00:45:29.500 to move forward. 00:45:29.500 --> 00:45:31.480 It's the same thing with the cell-- 00:45:31.480 --> 00:45:35.110 where the cell is moving forward, they're no ligands. 00:45:35.110 --> 00:45:37.720 And there's no F-actin. 00:45:37.720 --> 00:45:43.120 That principle is crucial also in changing 00:45:43.120 --> 00:45:44.410 cell shape and sheets. 00:45:44.410 --> 00:45:46.420 It's a little more complicated. 00:45:46.420 --> 00:45:53.650 But, again, there are receptors that interact with Rho GPTases, 00:45:53.650 --> 00:45:56.560 change the cytoskeleton and cell sheets 00:45:56.560 --> 00:45:59.540 and change the shape of the cell sheets. 00:45:59.540 --> 00:46:02.050 And this is really the molecular underpinning 00:46:02.050 --> 00:46:07.210 that will get those single cells to form tubes and bench sheets 00:46:07.210 --> 00:46:10.480 and all of the materials that are needed to build organs. 00:46:10.480 --> 00:46:12.660 And we'll stop there.