An anatomical spectrum of ciliopathy in Jbts17 knockout mice: craniofacial dysmorphology, polydactyly and forebrain anomalies
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Primary cilia orchestrate key developmental signaling pathways, and their dysfunction causes multisystem disorders collectively termed ciliopathies that often present with structural anomalies of the face, limbs, and brain. JBTS17 encodes a cilia associated scaffold required for proper ciliogenesis and ciliary signaling. Biallelic loss-of-function variants in JBTS17 are linked to Joubert spectrum disorders that include craniofacial malformations and polydactyly. To delineate the anatomical consequences of complete gene inactivation in vivo, we generated a CRISPR/Cas9 induced frameshift null allele of the murine Jbts17 locus. Late gestation Jbts17KO embryos showed ocular hypopigmentation with shallow optic cups, anterior craniofacial dysmorphology, and autopod polydactyly. Coronal brain sections revealed reduced cortical thickness with apparent ventriculomegaly, and the olfactory nerve was bilaterally absent at the level of the fila olfactoria. Mouse embryonic fibroblasts derived from knockout embryos displayed reduced Lis1 protein, consistent with a link between Jbts17 loss and Lis1 dependent cellular processes. These findings indicate that Jbts17 supports cilia dependent regional patterning in eye, craniofacial, and distal limb development and contributes to forebrain and olfactory development. The Jbts17 knockout provides a practical model of ciliopathy associated structural and neuroanatomical anomalies and an anatomical reference for subsequent quantitative and mechanistic studies
Abstract
Primary cilia orchestrate key developmental signaling pathways, and their dysfunction causes multisystem disorders collectively termed ciliopathies that often present with structural anomalies of the face, limbs, and brain. JBTS17 encodes a cilia associated scaffold required for proper ciliogenesis and ciliary signaling. Biallelic loss-of-function variants in JBTS17 are linked to Joubert spectrum disorders that include craniofacial malformations and polydactyly. To delineate the anatomical consequences of complete gene inactivation in vivo, we generated a CRISPR/Cas9 induced frameshift null allele of the murine Jbts17 locus. Late gestation Jbts17KO embryos showed ocular hypopigmentation with shallow optic cups, anterior craniofacial dysmorphology, and autopod polydactyly. Coronal brain sections revealed reduced cortical thickness with apparent ventriculomegaly, and the olfactory nerve was bilaterally absent at the level of the fila olfactoria. Mouse embryonic fibroblasts derived from knockout embryos displayed reduced Lis1 protein, consistent with a link between Jbts17 loss and Lis1 dependent cellular processes. These findings indicate that Jbts17 supports cilia dependent regional patterning in eye, craniofacial, and distal limb development and contributes to forebrain and olfactory development. The Jbts17 knockout provides a practical model of ciliopathy associated structural and neuroanatomical anomalies and an anatomical reference for subsequent quantitative and mechanistic studies