Building a Bigger Brain: Centriole Control of Cerebral Cortical Development
View/ Open
Hu_gsas.harvard.inactive_0084L_11765.pdf (14.94Mb)
Access Status
Full text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.Author
Metadata
Show full item recordCitation
Hu, Wen Fan. 2014. Building a Bigger Brain: Centriole Control of Cerebral Cortical Development. Doctoral dissertation, Harvard University.Abstract
Human genetics has identified essential roles for many centriole- and cilia-related proteins during human development. Mutations in centrosome-associated genes commonly cause microcephaly, or "small brain," and mutations in cilia-associated genes cause a diverse spectrum of diseases termed "ciliopathies." However, the functional relationships between these two crucial organelles are less well studied.The activities of centrosome-related proteins during mitosis and cytoskeletal remodeling are well-characterized, but their in vivo functions are incompletely understood. Here, we identify novel human mutations in a centrosomal gene which encodes a regulatory subunit of a microtubule interacting protein, and uncover unexpected pathways during vertebrate development. Human mutations cause severe microlissencephaly, reflecting defects in cerebral cortical neurogenesis, and loss of function in mice and zebrafish confirm essential roles in embryonic development, neurogenesis, and cell survival. Surprisingly, null mutant embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. Deficient induced pluripotent stem cells and lymphoblasts show defective proliferation and spindle structure, while deficient fibroblasts also demonstrate a remarkable excess of centrioles, including excessive maternal centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal novel roles for this protein in regulating overall centriole number, mother centriole and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.
Citable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070046
Collections
- FAS Theses and Dissertations [6136]
Contact administrator regarding this item (to report mistakes or request changes)