The ciliary kinesin KIF7 controls the development of the cerebral cortex by acting differentially on SHH signaling in dorsal and ventral forebrain.

Abstract

Mutations of <i>KIF7</i>, a key ciliary component of Sonic Hedgehog (SHH) pathway, are associated in humans with cerebral cortex malformations and clinical features suggestive of cortical dysfunction. KIF7 regulates the processing of GLI-A and GLI3-R transcription factors in a SHH-dependent manner both in humans and in mice. Here, we examine the embryonic cortex development of a mouse model that lacks the expression of KIF7 (<i>Kif7^-/-</i>). The cortex is composed of principal neurons generated locally in the dorsal telencephalon where SHH expression is low and inhibitory interneurons (cIN) generated in the ventral telencephalon where SHH expression is high. We observe a strong impact of <i>Kif7</i> deletion on the dorsal cortex development whose abnormalities resemble those of GLI3-R mutants: subplate cells are absent, the intermediate progenitor layer and cortical plate do not segregate properly, and corticofugal axons do not develop timely, leading to a delayed colonization of the telencephalon by thalamocortical axons. These structural defects alter the cortical distribution of cIN, which moreover exhibit intrinsic migration defects and cortical trajectories resembling those of cyclopamine-treated cIN. Our results show that <i>Kif7</i> deletion impairs the cortex development in multiple ways, exhibiting opposite effects on SHH pathway activity in the developing principal neurons and inhibitory interneurons.