BCS/NSC 249 Developmental Neurobiology Mary Wines-Samuelson

1. BCS/NSC 249 Developmental Neurobiology Mary Wines-Samuelson Email: mary_wines-samuelson@urmc.rochester.edu Textbook: Development of the Nervous System Sanes, Reh, and Harris Lectures on Blackboard; non-textbook reading materials

7. NSC 249--first part Jan. 16: Course overview and a discussion of gene regulation as it applies to neural development NO CLASS ON 1/21/19 (MLK Day) Jan. 23: Neural induction and regionalization I Jan. 28: Neural induction and regionalization II Jan. 30: Neurogenesis, migration and differentiation in the nervous system I Feb. 4: Neurogenesis, migration and differentiation in the nervous system II Feb. 6: Neurogenesis, migration and differentiation in the nervous system III Feb. 11: Regulation of neurogenesis in primate brain Feb. 13: Neurite outgrowth and pathfinding I Feb. 18: Neurite outgrowth II End of material for Exam I Feb. 20: EXAM I

8. Key points of today’s lecture: -Historical concepts of development -Fate restriction vs. pluripotency -Genetic control of differentiation (intrinsic fate) -Extrinsic fate determinants (morphogens) -Cell polarity and asymmetry -Intro to gastrulation as prerequisite for neural development

9. Development and disease: on the battlefront

10. Patient’s own hemato- poietic stem cells returned after chemo to reboot immune system

11. The origins of developmental biology -Hippocrates in 5th cent BC: “heat, wetness, solidification” -Aristotle in 4th cent BC: How are different parts formed? a) Preformationism b) Epigenesis (“upon formation”), or sequential generation of new structures *This debate lasted for over 2000 years! FINALLY… cell theory developed (1820-1880) Schleden (botanist) & Schwann (physiologist): All living things are derived from cells

12. Early debates regarding development centered on preformationism vs. epigenesis Homunculus in sperm head (1694) 

13. Weismann’s mosaic theory Radical idea: germ cells determine embryo characteristics (somatic vs. germline) -believed that nuclei divided asymmetrically to give rise to lineages with different cell fates… New debate! *a botanist monk would show that chromosomes determine inheritance of traits (Boveri & Sutton)

14. Initial experiment by Roux supported the mosaic model -”killed” one blastomere  half-embryo; thus, critical fate determinants missing

15. Later work by Dreisch was inconsistent with mosaic model *1st demonstration of regulation: embryo’s ability to develop normally despite missing or rearranged parts

16. Repression of genetic expression can be reversed by changing the cytoplasmic environment *Thus, development must also involve some ability of cells to respond to a new context= plasticity (or adaptability) *Development = a progression of fate restrictions?

17. Fate restriction over time during brain development

18. Genes are turned on/off by protein complexes bound to promoter Transcription requires: 1) open chromatin conformation state; 2) TATA box for RNA polymerase; 3) activators binding to enhancer elements in the 5’ UTR; and 4) RNA polymerase.

19. Correct spatial and temporal control of gene expression and protein synthesis is essential during development

20. Regulatory regions (promoters) determine tissue-specific gene expression pancreas pituitary -mouse transgene with GH (pituitary) under the control of the mouse elastase gene (in pancreas) turns on GH in pancreas

21. Neural fate determination via: a) extrinsic signal, b) autocrine/paracrine signal, c) receptor-mediated signal transduction, & d) intrinsic determinant

22. Sequestration of signaling factors determines fate after mitosis

23. Mechanisms of cell fate determination

24. Direct cell-cell (lateral) signaling can occur by: • Diffusible ligand-receptor interaction • Transmembrane ligand-receptor interaction • Direct diffusion of factors across gap junctions

25. Glucocorticoid receptor binding to hormone activates nuclear translocation & transcription *estrogen/tamoxifen-ER: used to generate inducible transgenics

26. Another level of control: one TF (gene) can activate or repress other genes, depending on promoter context

28. One mode of maintaining gene activation: positive autoregulation

29. Inducing signals and competent tissue present during gastrulation *results are time-sensitive!

30. How does the embryo know its head from its tail? D R P A L V Key: A= anterior P= posterior D= dorsal V= ventral A: Organizers

31. Localized determinants and asymmetric cell divisions establish the body plan of the early embryo

32. Gastrulation initiates at the blastopore (posterior), & extends anteriorly

33. Development of the amphibian from the blastula to neurula blue= mesoderm red= neurectoderm Axis/germ layer specification

34. Mesoderm induces neural signaling in ectoderm; default is epidermis

35. Neural crest arises from the dorsal seam of the newly-formed neural tube

37. Spemann and Mangold implicate the dorsal lip of the blastopore in neural induction