Novel links between ciliopathies and FGF-related craniofacial syndromes

K Liu1*, JT Tabler1, HL Szabo-Rogers1, A Mesbahi1, C Healy1, W Barrell1, B Wlodarczyk2, Author Affiliations 1 King's College London, UK 2 University of Texas Southwestern, USA 3 University of Texas at Austin, USAOral Presentation : Recent studies suggest that planar cell polarity (PCP) genes coordinate cell polarity, ciliogenesis and signalling during mammalian development. FUZ is a PCP gene implicated in human congenital anomalies, including neural tube defects and orofacial clefting. Our analysis of fuzzy mutant mice reveals ciliogenesis defects in craniofacial tissues as well as a suite of phenotypes reminiscent of FGF-related craniofacial disorders. Mutants have coronal synostosis, shortened facial extensions, low-set ears and a high-arched palate. To our surprise, we found that the facial defects are due to increased neural crest migration into the first branchial arch (BA1), resulting in maxillary hyperplasia. Furthermore, the neural crest cells migrate in a disorganized fashion, deeper than normal and with fewer cell-cell contacts. This ectopic migration correlates with a dramatic increase in FGF signaling, first in the mid-hindbrain boundary, and then in the BA1 epithelia. The increased tissue causes a medial positional shift in the palatal primordia that manifests as a high-arched palate with pseudo-cleft. Genetic loss of fgf8 rescues the maxillary hyperplasia. Taken together, our data suggest a novel interplay between ciliogenesis, FGF signalling and migration of neural crest which may underlie congenital craniofacial dysmorphologies.Molecular [email protected]

PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick central nervous system and in cultured myoblasts, Notch-stimulated cells were allowed to undergo differentiation. PKCζ phosphorylates membrane-tethered forms of Notch and regulates two distinct routing steps, depending on the Notch activation state. When Notch is activated, PKCζ promotes re-localization of Notch from late endosomes to the nucleus and enhances production of the Notch intracellular domain, which leads to increased Notch activity. In the non-activated state, PKCζ instead facilitates Notch receptor internalization, accompanied with increased ubiquitylation and interaction with the endosomal sorting protein Hrs. Collectively, these data identify PKCζ as a key regulator of Notch trafficking and demonstrate that distinct steps in intracellular routing are differentially modulated depending on Notch signaling status