Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome

Abstract

The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear1–3. In order to investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome gene4,5. These mice exhibit cerebellar hypoplasia with a vermis/midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome gene, Cep2906,7. Further, fetal magnetic resonance imaging (MRI) from human subjects with Joubert syndrome reveals a similar midline cleft suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling8. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1 mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist9, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome, which can be overcome with Wnt stimulation.

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

“…We and others have previously shown that, in mice, selective genetic ablation of genes required for cilia formation (Kif3A, Ift88, or Ftm) in GCP leads to ataxia and cerebellar hypoplasia caused by impaired Shh-dependent GCP proliferation (8,9,25). Cep290 KO mice, however, have only a mild cerebellar phenotype that mainly results from Shh-independent mechanisms (10).…”

“…So far, the largest number of ciliopathies is caused by mutations in CEP290/NPHP6 (17), and genetic abrogation of Cep290 in mice leads to mild cerebellar hypoplasia (10). The Cep290 transcript is expressed in GCPs and their progeny (18), but the subcellular location of the protein in mouse and human cerebellum is still unknown.…”

“…Interestingly, in ciliary conditional mutant mice, the cerebellum is hypoplastic and Sonic hedgehog (Shh)-dependent proliferation of granule cell progenitors (GCPs) is severely reduced, as in mice in which the JS-associated gene RPGRIP1L has been abrogated, suggesting that cilia-related defects in Shh-induced GCP expansion might explain the cerebellar abnormalities observed in JS (7)(8)(9). In contrast, Shh-dependent GCP proliferation and cerebellar structure were only mildly affected in Ahi1 or Cep290 KO mice, in which cilia formation is not modified (10). Thus, the analysis of ciliary mutants and JS/MKS mice models yields antagonistic hypotheses on the involvement of Shh-driven GCP proliferation in the etiology of the human forms of the syndromes.…”

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

“…By contrast, CEP290 mutant mice are viable. Hypomorphic alleles cause retinal degeneration and impaired olfaction [137,138], whereas null animals exhibit a defective cerebellar midline fusion [139]. In humans, BBS4 mutations cause BBS characterized by retinal dystrophy, obesity, cognitive impairments and renal malformation [140].…”

Le cil primaire, orchestrateur de la morphogenèse cérébrale

“…Par ailleurs, l'hydrocéphalie des souris Bbs1 M390R/M390R , caractérisées par la mutation la plus fréquemment identifiée chez les patients BBS, peut être partiellement corrigée (50 %) par l'administration de lithium aux mères pendant la gestation [52]. Le lithium avait déjà été mentionné comme agoniste de la voie Wnt, capable de corriger des défauts de prolifération au niveau du cervelet, chez le mutant Ahi1 [53]. L'ion lithium est connu pour ses effets pléiotropes : il agit notamment sur la régulation de l'activité de la sérine thréo-nine kinase, GSK3 (glycogen synthase kinase 3b), impliquée, entre autres, dans les voies de signalisation PDGF (plateled-derived growth factor a), Wnt/-caténine et dans le clivage de Gli3 (voie Hh).…”