New cellular functions for the Lowe Syndrome phosphoinositide phosphatase dOCRL in diverse Drosophila tissues. Sarah A Biber, Abdulmuhsen Ali, Avital Rodal. Biology Department, Brandeis University, Waltham, MA.

   Lowe syndrome is an X-linked disorder caused by mutations in OCRL (Oculocerebrorenal Syndrome of Lowe), a phosphatidylinositol 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 numerous 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 neuromuscular junction defects. Consistent with mammalian studies, our data indicates that dOCRL localizes to early endosomes and partially co-localizes with the PH domain-containing protein dSes/CG12393. In addition, we have uncovered a potential new role for dOCRL in nuclei. dOCRL localizes to S2 cell nuclei as well as to larval brain, salivary gland and garland cell nuclei. PI(4,5)P2, a preferred substrate of dOCRL, is known to localize to nuclei and to participate in chromatin remodeling and regulation of specific transcripts. dOCRL shuttles between the cytoplasm and the nucleus, and its nuclear localization appears to be negatively regulated by dSes and positively regulated by a non-canonical NLS sequence. Our findings suggest that dOCRL may perform multiple cellular functions in both the cytoplasm and nucleus. Drosophila is proving to be a useful model for gaining new insights into the complex mechanisms underlying the pathology of Lowe syndrome in diverse tissues.