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

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

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 ( ) Schleden (botanist) & Schwann (physiologist): All living things are derived from cells

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

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)

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

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

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?

Fate restriction over time during brain development

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

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

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

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

Sequestration of signaling factors determines fate after mitosis

Mechanisms of cell fate determination

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

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

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

One mode of maintaining gene activation: positive autoregulation

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

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

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

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

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

Mesoderm induces neural signaling in ectoderm; default is epidermis

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