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Title page for ETD etd-10072012-142025

Type of Document Dissertation
Author Doll, Caleb Andrew
Author's Email Address caleb.a.doll@vanderbilt.edu
URN etd-10072012-142025
Title Endoplasmic reticulum translocon function is required for dorsal diencephalic neurogenesis in the zebrafish
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
David Miller Committee Chair
Joshua Gamse Committee Member
Lila Solnica-Krezel Committee Member
Todd Graham Committee Member
  • neurogenesis
  • brain development
  • asymmetry
Date of Defense 2012-08-30
Availability unrestricted
The epithalamus of the zebrafish contains the dorsal habenulae (Dh), a bilateral pair of nuclei characterized by significant left-right asymmetries in gene expression, anatomy, and connectivity. A screen for mutations that affected habenular laterality identified a nonsense mutation in the sec61a-like 1(sec61al1) gene, which codes for the alpha subunit of the ER translocon, a vital entry point for the maturation and processing of all transmembrane and many secreted proteins. sec61al1 mutants undergo an altered program of neurogenesis, producing excess early-borne neurons of the lateral subnucleus at the expense of the later-borne medial subnucleus. Ultrastructural analysis of the cells lining the 3rd ventricle indicates that periventricular precursor cells, which form an epithelium in wild-type embryos, lose apical-basal polarity in sec61al1 mutants. Furthermore, trafficking of N-cadherin through the Sec61 translocon likely mediates differentiation of dorsal habenula progenitor cells, as morphants depleted for cdh2 (the gene that encodes the N-cadherin protein), also develop symmetric LsDh and cdh2 mutant progenitor cells preferentially contribute to the LsDh class. We conclude that Sec61al1 acts to maintain structural polarity in habenular precursor cells, in turn regulating the timing of asymmetric neurogenesis in the habenular nuclei: in the absence of Sec61al1, progenitor cells of the lateral subnucleus overproliferate and differentiate, ultimately resulting in symmetric habenular nuclei.
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