Centriolar protein PIBF1 is required for craniofacial and forebrain development.

Primary cilia are microtubule based extensions on the surface of most cells that play a crucial role in cellular signaling during development, tissue homeostasis, and organ function. Defective cilia result in a wide variety of clinical manifestations affecting multiple organ systems, collectively termed ciliopathies. Ciliopathies are rare, exhibit tremendous genetic diversity and an overlap of clinical features, making diagnosis and treatment challenging. Identifying and characterizing novel ciliary variants is critical to gain an improved understanding of ciliopathic pathologies. To address this need, we performed a forward genetic screen using N-ethyl-N-nitrosourea (ENU) mutagenesis and subsequent complementation analysis. We found a novel variant in Pibf1, a gene essential for ciliogenesis and previously linked to the ciliopathy, Joubert syndrome. Pibf1^m1Bei/Null embryos exhibited a collection of craniofacial anomalies associated with ciliopathies including midline defects, maxillary hyperplasia, micrognathia, and high arched palate. Interestingly, Pibf1^m1Bei/Null embryos also presented with semilobar holoprosencephaly, a phenotype not typically associated with ciliopathies. Molecular analysis revealed aberrant Shh expression and GLI3 processing concomitant with an expansion of Fgf8 and Lhx6 expression across structures in the face, brain, and oral cavity. In summary, these data suggest a role for PIBF1 and cilia in establishing proper SHH/FGF8 signaling axes across the embryo and suggest that holoprosencephaly is a part of the ciliopathic phenotypic spectrum associated with Joubert syndrome.