NIH Research Festival
The primary cilia function as sensory antennae and play a critical signaling role in the development of multiple organs. Disruption of ciliary function underlies a variety of human diseases collectively known as ciliopathies. Sonic Hedgehog (SHH) signaling is one of the pathways mediated through primary cilia and regulates central nervous system development . FKBP8 null mutation in mice was previously shown to cause constitutive activation of SHH signaling in the neural tube leading to profound developmental defects, but the mechanism by which FKBP8 affects SHH signaling was unclear. We show that cilia morphogenesis in the neural tube and in fibroblasts of FKBP8 null mice remains intact. However, adenylyl cyclase III fails to translocate to the ciliary membrane, thus abolishing cAMP synthesis and suppressing PKA activity. This leads to inhibition of the proteolytic processing of Gli transcription factors to the suppressor forms, which depends on PKA mediated phosphorylation. As generation of Gli repressors is quenched, SHH signaling in the cilia manifests constitutive activation, which explains the earlier observation in the FKBP null mutant mice. Using differentiated optic cups derived from FKBP8 null iPSCs, we were able to recapitulate this phenotype in photoreceptor connecting cilia. In summary, our study shows that the FKBP8 is essential for adenylate cycles to traffick into the cilia, and loss of FKBP8 disrupts ciliary signaling.
Scientific Focus Area: Cell Biology
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