Investigating the role of Rab34 in regulating Hedgehog signaling pathway activity.

Amelia Meles

Document Type

Article

Publication Date

Summer 2017

JAX Location

In: Student Reports, Summer 2017, Jackson Laboratory

Abstract

Rab34, a member of the Rab family of small GTPases, was previously identified as a direct target of the Gli family of transcription factors that function as the downstream effectors of Hedgehog (Hh) signaling pathway. Phenotype analysis of Rab34 mutant embryos conducted by the Knockout Mouse Project (KOMP) highlighted the potential role for Rab34 as a novel regulator of the Hedgehog signaling pathway. Here, we provide a preliminary characterization of developmental defects in observed in Rab34 mutant embryos and investigate its role in regulating Hh pathway through image-based analysis and in vitro assays. In addition to the previously characterized phenotypes, such as polydactyly, Rab34 mutants also display developmental heart position defects, delayed endochondral ossification, and impaired cranio-facial formation. Further, we found that Rab34 mutants display lower signaling levels in response to pathway stimulation, but contain increased levels of unprocessed full-length Gli2 and Gli3. We hypothesize Rab34 may play role in trafficking Gli2 and Gli3 to the proteasome or be involved in post-translational processing of Gli2/3 such that impaired Rab34 function would lead to reduced gene repression via accumulation of inactive Gli3FL. This model would account for the loss of signaling activity in response to agonist even though there is accumulation of Gli2 and Gli3 full length forms. Additionally, it is probable that Rab34 influences primary cilia assembly or trafficking because mutant mouse embryonic fibroblasts display reduced cilia formation.

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