Show simple item record

dc.contributor.advisorDymecki, Susan M.
dc.contributor.authorYang, Peter
dc.date.accessioned2014-02-25T17:52:35Z
dash.embargo.terms2020-03-31
dc.date.issued2014-02-25
dc.date.submitted2013
dc.identifier.citationYang, Peter. 2014. Central role for Sonic hedgehog-triggered pericytes in hindbrain choroid plexus development. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:11225en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11744423
dc.description.abstractThe choroid plexus is an organ within each brain ventricle comprised of elaborate folds of epithelium (CPe) and vasculature. It performs numerous functions essential for brain development and health, including secretion of cerebrospinal fluid (CSF) and acting as the blood-CSF barrier. Functionality requires: (1) that CPe and vasculature develop in register and in close proximity, so that the CPe ensheaths the vasculature at a high surface area to volume ratio, which permits efficient CSF secretion; and (2) that CPe barrier integrity is sustained throughout choroid plexus expansion. Genetic experiments in mouse embryos have identified a central role for Sonic hedgehog (Shh) in coordinating these developmental challenges. Specifically, Shh is secreted by differentiated CPe and drives choroid plexus expansion. In the absence of Shh, a hypoplastic choroid plexus forms, which is deficient in CPe, vasculature, and villous folds. Two choroid plexus cell populations respond to Shh: (1) rhombic lip-resident CPe progenitor cells and (2) vascular pericytes. Here, I present evidence that canonical Shh signaling to CPe progenitors alone is insufficient to fully drive their proliferation at normal rates. Rather, Shh-triggered pericytes appear to secondarily boost CPe progenitor cell proliferation, in addition to acting in vascular development. Shh-triggered pericytes also appear necessary for formation of the characteristic folds of the choroid plexus. Thus, pericytes coordinate the expansion of choroid plexus epithelium and vasculature. Notch signaling was also explored and was found to inhibit the differentiation of CPe progenitors, maintaining them in a proliferative state. Notch activation in CPe progenitors leads to invaginated tubules from the overproliferating CPe progenitor domain, without associated vascular growth or villous folds. Folding morphogenesis may thus be regulated by vascular components such as pericytes, and require that vascular growth match CPe growth. To identify Shh-induced pericyte signaling programs that might underlie these developmental processes, expression profiling was performed on dsRed-labeled pericytes isolated from Shh-deficient versus wild-type choroid plexuses. Candidate genes, including several involved in lipid metabolism, were identified. Collectively, this work points to pericytes as central in orchestrating the coordinated elaboration of multiple choroid plexus cell types, producing the complex tissue architecture required for efficient CSF production.en_US
dc.language.isoen_USen_US
dash.licenseLAA
dc.subjectGeneticsen_US
dc.subjectDevelopmental biologyen_US
dc.subjectBiologyen_US
dc.subjectChoroid plexusen_US
dc.subjectDevelopmenten_US
dc.subjectEpitheliumen_US
dc.subjectNotchen_US
dc.subjectPericyteen_US
dc.subjectSonic hedgehogen_US
dc.titleCentral role for Sonic hedgehog-triggered pericytes in hindbrain choroid plexus developmenten_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorYang, Peter
dash.embargo.until2020-03-31
dc.date.available2014-02-25T17:52:35Z
thesis.degree.date2014en_US
thesis.degree.disciplineBiology: Medical Sciences, Division ofen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberD'Amore, Patriciaen_US
dc.contributor.committeeMemberLehtinen, Mariaen_US
dc.contributor.committeeMemberSive, Hazelen_US
dc.contributor.committeeMemberDrummond, Iainen_US
dash.contributor.affiliatedYang, Peter


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record