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

5. NSC 249--first third
Jan. 18: Course overview and a discussion of gene regulation as it applies to neural development (MWS)
Jan. 23: Neural induction and regionalization I (MWS)
Jan. 25: Neural induction and regionalization II (MWS)
Jan. 30: Neurogenesis, migration and differentiation in the nervous system I (MWS)
Feb. 1: Neurogenesis, migration and differentiation in the nervous system II (MWS)
Feb. 6: Neurogenesis, migration and differentiation in the nervous system III (MWS)
Feb. 8: Regulation of neurogenesis in primate brain (Dr. David Kornack)
Feb. 13: Neurite outgrowth and pathfinding I (MWS)
Feb. 15: Neurite outgrowth II (MWS) end of material for Exam I
Feb. 20: EXAM I

6. 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
progression of new structures
*This debate lasted for 1400 years!
FINALLY… cell theory developed ( )
Schleden (botanist) & Schwann (physiologist): All living things
are derived from cells

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

8. 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)
The cell theory made preformationism untenable and the debate switched to how cells become specialized

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

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

11. *Development = a progression of fate restrictions?
Repression of genetic expression can be reversed by changing the cytoplasmic environment
----- Meeting Notes (1/14/15 13:46) -----
*Thus, development must also involve some ability of cells to respond to a new context= plasticity (or adaptability)
*Development = a progression of fate restrictions?

12. Fate restriction over time during brain development

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

14. 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.

15. 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

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

17. Sequestration of
signaling factors
determines fate after mitosis

18. Mechanisms of cell fate determination
A: Proximity to external signal source; B: activation of autocrine/paracrine signaling via endocrine gland; C: signaling via activation of receptor/signaling cascade; D: intrinsic signal coupled with controlled mitosis

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

20. *estrogen/tamoxifen-ER: used to generate inducible transgenics
Glucocorticoid receptor binding to hormone activates nuclear translocation & transcription
Another example: estrogen/ER. We utilize this system to make inducible transgenic animals.
Chap 9 Wolpert
*estrogen/tamoxifen-ER: used to generate inducible transgenics

21. Another level of control: one TF (gene) can activate or repress other genes, depending on promoter context
Chap.9 Wolpert

23. One mode of maintaining gene activation: positive autoregulation
Fig 9.8: Continued expression of gene regulatory proteins maintains a pattern of gene activity

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

25. Heritability: the proportion of phenotypic variance due to genetic variance
P= G + E;
h2= genotypic variance/phenotypic variance (or g + e)

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

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

29. Neural crest arises from the dorsal seam of the newly-formed neural tube
Neural crest migration requires disruption of the basement membrane around the neural tube (to release the cells), as well as downregulation of their cadherins (adhesion proteins). Neural crest migrating over the somites will become sensory nerves and the autonomic nervous system; neural crest migrating dorsally will give rise to pigmented cells.

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

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