A new mouse ciliopathy with a deletion in the Talpid3 gene, first identified in chicken

We have generated a Talpid3 mutant mouse by deleting a highly conserved region of the Talpid3 gene using the Cre-loxP system. A mutation in Talpid3 is responsible for the chicken talpid3 mutant phenotype, which includes embryonic lethality, polydactylous limbs, dorsalized neural tube and polycystic kidneys. Similar phenotypes are seen in human syndromes with mutations in genes encoding centrosomal or intraflagella transport proteins leading to defects in ciliogenesis. Chicken Talpid3 localizes to the centrosome and cells of chicken talpid3 mutants lack primary cilia. Analysis of the chicken Talpid3 protein identified a highly conserved region, required to rescue ciliogenesis and sufficient for centrosomal localisation. Constitutive removal of this highly conserved region in mouse results in lack of primary cilia, embryonic lethality, pericardial oedema and abnormal heart looping. Conditional removal of this region in the developing mouse limb bud results in abnormal expression of Hh target genes, leading to short polydactylous limbs with abnormal ossification. We can use the talpid3 mutant mouse mutant to conditionally remove cilia in different tissues or at different times to further our understanding of the role of cilia in development and cross with other ciliopathy mutants to test genetic interactions between Talpid3 and other genes required for ciliogenesis.