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

2. Jan. 13: Course overview and a discussion of gene regulation as it applies to neural development (MWS) Jan. 18: NO CLASS (MLK Day) Jan. 20: Neural induction and regionalization I (MWS) Jan. 25: Neural induction and regionalization II (MWS) Jan. 27: Neurogenesis, migration and differentiation in the nervous system I (MWS) Feb. 1: Neurogenesis, migration and differentiation in the nervous system II (MWS) Feb. 3: Neurogenesis, migration and differentiation in the nervous system III (MWS) Feb. 8: Regulation of neurogenesis in primate brain (Dr. David Kornack) Feb. 10: Neurite outgrowth and pathfinding I (MWS) Feb. 15: Neurite outgrowth II (MWS) end of material for Exam I Feb. 17: EXAM I NSC 249--first third

3. The origins of developmental biology -Hippocrates in 5 th cent BC: “heat, wetness, solidification” -Aristotle in 4 th cent BC: How are different parts formed? a) Preformationism b) Epigenesis (“upon formation”), or progression of new structures *This debate lasted for 1400 years! FINALLY… cell theory developed (1820-1880) Schleden (botanist) & Schwann (physiologist): All living things are derived from cells

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

5. 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)

6. Initial experiment by Roux appeared to support the mosaic model -”killed” one blastomere  half-embryo; thus, critical fate determinants missing

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

8. 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?

9. Fate restriction over time during brain development

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

11. 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. Genes are turned on/off by protein complexes bound to promoter

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

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

14. Sequestration of signaling factors determines fate after mitosis

15. Mechanisms of cell fate determination

16. Direct cell-cell (lateral) signaling can occur by: 1)Diffusible ligand- receptor interaction 2)Transmembrane ligand-receptor interaction 3)Direct diffusion of factors across gap junctions

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

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

20. One mode of maintaining gene activation: positive autoregulation

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

22. Heritability: the proportion of phenotypic variance due to genetic variance P= G + E; h 2 = genotypic variance/phenotypic variance (or g + e)

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

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

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

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

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