Mice with a conditional deletion of Talpid3 (KIAA0586) – a model for Joubert syndrome

Abstract

Joubert syndrome (JS) is a ciliopathy associated with mutations in numerous genes encoding cilia components. TALPID3 encoded by KIAA0856 in man (2700049A03Rik in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in KIAA0856 have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11–12 of Talpid3 in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. Talpid3 mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre‐derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in Wnt7a expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of Talpid3. The Talpid3 conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for Talpid3 in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

A new mouse model for the neurodevelopmental ciliopathy Joubert syndrome

“…So, a simple correlation between severity of ciliogenesis defects and severity of CNS malformation does not appear to apply. Bashford and Subramanian further show an effect on Hedgehog signaling in their Talpid3 cKO model, with decreased levels of Gli1, Ptch1, and Gli2A but increased Gli3R . These findings, together with previous work showing the importance of primary cilia for Hedgehog signaling, and of Hedgehog signaling for cerebellar granule cell proliferation, support dysregulation of this pathway as the major mechanism causing the hypoplastic vermis seen in JBTS patients.…”

“…The article by Bashford and Subramanian presents a conditional Talpid3 knockout mouse with a cerebellar phenotype reminiscent of the human hindbrain malformation . Talpid3 cKO mice display ataxia and a markedly hypoplastic cerebellum with a significantly smaller vermis, similar to findings in patients with JBTS.…”

“…In this issue of The Journal of Pathology , Bashford and Subramanian describe a new mouse model for the neurodevelopmental ciliopathy Joubert syndrome (JBTS). The relevance of studying this rare disorder lies in its link to primary cilia, small organelles whose key role in human development and disease has become obvious in recent years and is illustrated by the increasingly large group of disorders called ciliopathies.…”

“…The role of cilia on developing and mature neurons and the precise pathomechanisms leading from dysfunctional primary cilia to CNS dysfunction and malformations are only partly understood to date. The article by Bashford and Subramanian presents a detailed description of the CNS phenotype of a new conditional mutant in KIAA0586/TALPID3 , one of the genes associated with JBTS.…”

“…Abnormal cerebellar development in a new mouse model for JBTS. Cerebellar findings in Talpid3 conditional knockout (cKO) mice compared with wild‐type at early and later stages of cerebellar development: Bashford and Subramanian describe loss of cilia (red) on granule cell progenitors (GCPs) and granule cells (GCs) in the external granule cell layer (EGL) and the internal granule cell layer (IGL). At early stages, the EGL is thinner in mutants with a decreased density of GCPs (grey cells), decreased proliferating GCPs (blue), and increased apoptotic GCPs (black).…”