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Hum Mol Genet. 2019 Mar 15;28(6):877-887. doi: 10.1093/hmg/ddy392.

Altered GLI3 and FGF8 signaling underlies acrocallosal syndrome phenotypes in Kif7 depleted mice.

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Centre de Recherche en Neurosciences de Lyon, Équipe GENDEV, INSERM U1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, Lyon, France.
Service de Génétique et Centre de Référence des Anomalies du Développement de la Région Auvergne-Rhône-Alpes, CHU de Lyon, France.
Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U-1217, Lyon, France.
Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR1163, Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Department of Histology-Embryology and Cytogenetics, Necker Hospital, AP-HP, Paris, France.


Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by agenesis or hypoplasia of corpus callosum (CC), polydactyly, craniofacial dysmorphism and severe intellectual deficiency. We previously identified KIF7, a key ciliary component of the Sonic hedgehog (SHH) pathway, as being a causative gene for this syndrome, thus including ACLS in the group of ciliopathies. In both humans and mice, KIF7 depletion leads to abnormal GLI3 processing and over-activation of SHH target genes. To understand the pathological mechanisms involved in CC defects in this syndrome, we took advantage of a previously described Kif7-/- mouse model to demonstrate that in addition to polydactyly and neural tube closure defects, these mice present CC agenesis with characteristic Probst bundles, thus recapitulating major ACLS features. We show that CC agenesis in these mice is associated with specific patterning defects of the cortical septum boundary leading to altered distribution of guidepost cells required to guide the callosal axons through the midline. Furthermore, by crossing Kif7-/- mice with Gli3Δ699 mice exclusively producing the repressive isoform of GLI3 (GLI3R), we demonstrate that decreased GLI3R signaling is fully responsible for the ACLS features in these mice, as all phenotypes are rescued by increasing GLI3R activity. Moreover, we show that increased FGF8 signaling is responsible in part for CC defects associated to KIF7 depletion, as modulating FGF8 signaling rescued CC formation anteriorly in Kif7-/- mice. Taken together our data demonstrate that ACLS features rely on defective GLI3R and FGF8 signaling.


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