Cell Type Nervous System I. Developmental Readout. Foundations. Stem cells. Organ formation. Human issues.

Transcription

1 Cell Type Nervous System I Human issues Organ formation Stem cells Developmental Readout Axes Cell type Axon guidance 3D structure Analysis Model + + organisms Foundations Principles 1

2 What is the nervous system? Diagram of a motor neuron neuron 2

3 2 Gilbert 12.3 Primary neurulation: neural tube formation in the chick embryo (Part 1) 3 Gilbert 12.3 Primary neurulation: neural tube formation in the chick embryo (Part 2) 3

4 4 Gilbert 12.2 Neurulation in a chick embryo (dorsal view) (Part 1) 5 Gilbert 12.2 Neurulation in a chick embryo (dorsal view) (Part 2) 4

5 Regionalization versus general neural 6 Gilbert 12.9 Early human brain development 5

6 7 Gilbert Development of the human spinal cord (Part 2) What region of the embryo forms the nervous system? 6

7 8 Ectoderm epidermis nervous system Mesoderm muscle blood kidney heart Purves 20.9 Germ Embryonic layer fates Germ Layers Endoderm gut lung 9 Vertebrate fate maps at early gastrula stage 7

8 10 Drosophila neural fate map at early gastrula Technau Fate mapping shows what cells will become Experiment: inject non-diffusible dye, ask what labeled area becomes early blastula early neurula Conclusion: labeled area is destined to become neurons in eye and brain hatched tadpole 8

9 12 When do cells decide on their fate? Explant experiment: remove same relative region culture in saline, later, assay fates early blastula late blastula early neurula epidermis epidermis many neurons Conclusion: cell fate decision is made by neurula Also assay via transplant assays, gene expression 13 Induction assay for potency Remove few cells culture +/- inducers, later, assay fates early blastula no inducer plus inducers epidermis Conclusion: Early blastula cells are multipotent muscle, neuron blood, pancreas 9

10 Early neural signaling/genes 14 Wilson et al,

11 15 DISPERSED ANIMAL CAP BMP4 Inhibition of BMP signaling activates neural gene expression Wilson et al, Xenopus SoxD is expressed from early gastrula and in response to BMP inhibition Mizueki et al,

12 17 con BD- con BD- BD- is a dominant negative SoxD BDcon BD- con Xenopus SoxD is required for expression of some early neural genes Mizueki et al, Ectopic SoxD induces ectopic expression of neural genes Mizueki et al,

13 19 Neuroblast clusters Technau, Neuroblast lineages differ in different regions Technau,

14 21 SoxN is expressed in the developing nervous system RNA protein Buescher et al SoxN required for normal neuroblast development Buescher et al

15 23 SoxN is required for lateral and intermediate neuroblasts Buescher et al = early gastrula Zic1 is a very early neural marker gene Kuo et al,

16 25 Geminin is an early neural gene that inhibits differentiation and promotes cell cycle withdrawal Seo et al, 2006 Proneural genes 16

17 26 Basic helix loop helix proteins Bertrand et al Proneural bhlh gene family Bertrand et al

18 28 Proneural genes bind E boxes Bertrand et al Regulation of Ac/Sc gene targets Bertrand et al

19 30 Ma et al, 1996 Expression of neurogenin, neurod in presumptive primary neurons of Xenopus 31 Ma et al,

20 32 Bertrand et al 2002 Role of Notch 20

21 33 CSL = CBF1/SuH/Lag Notch pathway Lai, Lai, 2004 Drosophila Xenopus 21

22 35 Relationship of proneural gene expression and Notch signaling Chitnis and Kintner, Bertrand et al

23 Role of inhibitors See the comment_on_mandel pdf posted with this section. 37 Cycling progenitor Differentiating neuron RE-1 Silencing Factor (REST) (neural cell restrictive factor (NCRF)) mechanism 23

24 38 Stem cell Lineage Restricted progenitor Differentiated neuron REST downregulation during neurogenesis Ballas et al, Comment on Mandel,

25 Role of asymmetric cell division This will be covered further in the papers you read. I am posting a review from Wodarz that covers some of this material. See also Gilbert, chapter Gilbert Neural stem cells in the germinal epithelium (Part 2) basal apical 25

26 Differentiation of the walls of the neural tube (Part 3) 42 Asymmetric neuroblast cell division/ role of epithelium Siegrist and Doe,

27 43 Asymmetric gene expression during neuroblast division polarize spindle orientation Wodarz,