Ofd1 Controls Dorso-Ventral Patterning and Axoneme Elongation during Embryonic Brain Development

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.

Small organelle, big responsibility: the role of centrosomes in development and disease

“…Loss-of-function studies in mice show a genderdependent effect of Ofd1 inactivation; hemizygous males die during gestation probably as a result of neural tube closure failure, whereas heterozygous females die at birth exhibiting abnormalities in oral and facial structures (table 1) [132]. On the cellular level, ciliary axoneme elongation is defective in the developing forebrain of mutant females despite basal bodies being able to dock normally to the plasma membrane [133]. These models recapitulate many of the phenotypes of human oral-facial-digital syndrome type 1, which also exhibits an X-linked dominant male-lethal trait [134].…”

The role of primary cilia in the development and disease of the retina

“…34 OFD1 is a distal centriole protein that regulates the length of centrioles 35 and ciliary axonemes. 36 Mutations in OFD1 cause oro-facial-digital syndrome, non-syndromic RP, and RP as a feature of Joubert syndrome (JBTS). [37][38][39] ofd1 morphant zebrafish occasionally develop retinal coloboma.…”

A novel pathogenic variant in OFD1 results in X‐linked Joubert syndrome with orofaciodigital features and pituitary aplasia

“…Although the exact function of OFD1 gene is not fully understood, it has been established to play a crucial role in the control of dorso‐ventral patterning, forebrain development, and corticogenesis in embryonic life and in mouse models, OFD1 mutant mice exhibit ciliary dysfunction and abnormal Shh (Sonic Hedgehog) signaling (D'Angelo et al, ; Ferrante et al, ).…”