Abstract
Oral-facial-digital type I syndrome (OFDI) is a human X-linked dominant-male-lethal developmental disorder caused by mutations in the OFD1 gene. Similar to other inherited disorders associated to ciliary dysfunction OFD type I patients display neurological abnormalities. We characterized the neuronal phenotype that results from Ofd1 inactivation in early phases of mouse embryonic development and at post-natal stages. We determined that Ofd1 plays a crucial role in forebrain development, and in particular, in the control of dorso-ventral patterning and early corticogenesis. We observed abnormal activation of Sonic hedgehog (Shh), a major pathway modulating brain development. Ultrastructural studies demonstrated that early Ofd1 inactivation results in the absence of ciliary axonemes despite the presence of mature basal bodies that are correctly orientated and docked. Ofd1 inducible-mediated inactivation at birth does not affect ciliogenesis in the cortex, suggesting a developmental stage-dependent role for a basal body protein in ciliogenesis. Moreover, we showed defects in cytoskeletal organization and apical-basal polarity in Ofd1 mutant embryos, most likely due to lack of ciliary axonemes. Thus, the present study identifies Ofd1 as a developmental disease gene that is critical for forebrain development and ciliogenesis in embryonic life, and indicates that Ofd1 functions after docking and before elaboration of the axoneme in vivo.
Highlights
The forebrain is the most anterior part of the central nervous system (CNS) and derives from a simple layer of neuroepithelial cells, which becomes specified along the antero-posterior (AP) and dorsal-ventral (DV) axes by the action of various signalling molecules such as Sonic hedgehog (Shh) and Wnt family members [1].Recently, numerous studies have revealed that the primary cilium plays a crucial role in modulating critical signalling pathways during CNS development [2,3,4,5,6,7,8,9]
Ofd1D4–5/+ mutants display a phenotypic variability We assessed Ofd1 function during forebrain development and we found that Ofd1D4–5/+ heterozygous female mutants displayed a phenotypic variability that ranges from mild to severe
This is most probably due to the mosaicism expected for the X-inactivation phenomenon in mice, in which the amount of Ofd1 expressed in heterozygous females depends on which allele, and in which cell-type Ofd1 function is abolished
Summary
The forebrain is the most anterior part of the central nervous system (CNS) and derives from a simple layer of neuroepithelial cells, which becomes specified along the antero-posterior (AP) and dorsal-ventral (DV) axes by the action of various signalling molecules such as Sonic hedgehog (Shh) and Wnt family members [1].Recently, numerous studies have revealed that the primary cilium plays a crucial role in modulating critical signalling pathways during CNS development [2,3,4,5,6,7,8,9]. The cobblestone mutant, a hypomorphic allele of the IFT gene Ift, has severe defects in the formation of dorsomedial telencephalic structures, and abnormal AP and DV patterning. In this mutant, Gli proteolytic processing is reduced and an upregulation of canonical Wnt signalling in the neocortex and in the caudal forebrain can be observed [12]. Loss of Kif3a, a kinesin involved in the IntraFlagellar Transport leads to the degeneration of primary cilia, and disruption of Gli processing in the cerebral cortex [16] Taken together these studies illustrate a critical role for ciliary intraflagellar proteins during forebrain development [17]. Little is known on the role of ciliary basal body proteins during forebrain development
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