A Drosophila Model of Lowe Syndrome

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dc.contributor.advisor Rodal, Avital
dc.contributor.author Biber, Sarah
dc.date.accessioned 2014-09-04T00:02:59Z
dc.date.available 2014-09-04T00:02:59Z
dc.date.issued 2014
dc.identifier.uri http://hdl.handle.net/10192/28575
dc.description.abstract Lowe syndrome is an X-linked disorder caused by mutations in OCRL (Oculocerebrorenal Syndrome of Lowe), a phosphatidylinositol-5-phosphatase with previously identified roles in endocytic trafficking, phosphoinositide metabolism, cytokinesis, and cilium formation and function. However it is not understood how defects in the OCRL enzyme result in the debilitating neurological, kidney and eye symptoms that are prevalent in Lowe syndrome. We have taken advantage of the high conservation of OCRL between humans and insects to model Lowe syndrome in Drosophila melanogaster. Here we have generated a Drosophila OCRL (dOCRL) null mutant with deficiencies at both the cellular and tissue levels. Loss of dOCRL causes lethality in larval stages. Third instar larvae lacking dOCRL present with large melanotic masses, and hemocyte proliferation, differentiation and morphology defects. We thus decided to use the innate immune system as a novel arena for investigating the in vivo cellular functions of dOCRL and several of its conserved binding partners. Consistent with mammalian studies, our data indicates that dOCRL localizes to early endosomes and co-localizes with the PH domain-containing protein dSes/CG12393. Loss of dOCRL in hemocytes promotes multinucleation, which is consistent with knockdown experiments in mammalian and S2 cell cultures. dOCRL mutant hemocytes also present with massively up-regulated F-actin and significant increases in plasmatocyte spikiness. All of the observed defects in dOCRL hemocytes are rescued cell-autonomously. Furthermore, rescue is dependent on the phosphoinositide-5-phosphatase activity of dOCRL. Our findings suggest that hematopoietic phenotypes observed in the dOCRL mutant may result from changes in Toll signaling. This work has established and validated a new animal model of Lowe Syndrome and uncovered a potential new role for dOCRL in fly hematopoiesis and immunity.
dc.description.sponsorship Brandeis University, Graduate School of Arts and Sciences
dc.format.mimetype application/pdf
dc.language English
dc.language.iso eng
dc.publisher Brandeis University
dc.relation.ispartofseries Brandeis University Theses and Dissertations
dc.rights Copyright by Sarah Biber 2014
dc.subject Drosophila
dc.subject Lowe Syndrome
dc.subject phosphoinositide metabolism
dc.title A Drosophila Model of Lowe Syndrome
dc.type Thesis
dc.contributor.department Graduate Program in Molecular and Cell Biology
dc.degree.name PhD
dc.degree.level Doctoral
dc.degree.discipline Molecular and Cell Biology
dc.degree.grantor Brandeis University, Graduate School of Arts and Sciences

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