Mouse models of ciliopathies: the state of the art

Abstract

The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such as Meckel-Grüber syndrome (MKS), Joubert syndrome (JBTS), Bardet-Biedl syndrome (BBS) and Alström syndrome (ALS). Reflecting the manifold requirements for cilia in signalling, sensation and motility, different ciliopathies exhibit common elements. The mouse has been used widely as a model organism for the study of ciliopathies. Although many mutant alleles have proved lethal, continued investigations have led to the development of better models. Here, we review current mouse models of a core set of ciliopathies, their utility and future prospects.

The evolution and conservation of left-right patterning mechanisms

“…A snail-king is discovered in ∼1/20,000 specimens, closely matching the rate of situs inversus in humans (Brunner, 1999). Therefore, if one assumes that human embryos employ leftward flow for symmetry breakage, which is well justified on the basis of cilia mutants resulting in laterality syndromes (Goetz and Anderson, 2010;Norris and Grimes, 2012;Shiraishi and Ichikawa, 2012), both mechanisms appear equally reliable at first glance.…”

“…It has been estimated that congenital heart defects occur in up to 1% of live human births (Liu et al, 2013), of which some 3% are considered to arise from defects in the LR pathway (Sutherland and Ware, 2009). Individual ciliopathies (see Glossary, Box 2), a sizable number of which are associated with LR defects (Fliegauf et al, 2007;Gerdes et al, 2009;Norris and Grimes, 2012;Oh and Katsanis, 2012), tend to be relatively rare (≤10 −4 ). If these syndromes are considered in combination, it has been estimated that ∼1/300 humans is affected by some form of ciliopathy.…”

Sperm dysfunction and ciliopathy

“…This is not compatible with the symptoms of human ciliopathy, in which patients are alive and show fertility, making it possible to carry out family studies. Further experiments are necessary with mouse models, including analyses with extensive N-ethyl-N-nitrosourea mutants or dominant-negative mutants, and the engineering of human point mutations in mice [94]. Studies using Chlamydomonas and marine invertebrates also shed light on the molecular structure and mechanism of cilia and flagella, and on the genetic diagnosis of ciliopathy.…”

“…The BBSome and IFT are the transport systems of ciliary proteins at the base of the cilium and inside the cilium, respectively. Most mouse mutations in BBS genes are lethal, and the rest of the mutants show obesity, retinal degeneration, cystic kidneys or polydactyly [92][93][94]. Mutation in BBS2 or BBS4 causes male infertility due to the failure of sperm flagellar formation [95].…”

The primary cilium

“…This is certainly the case for inherited ciliopathies, where causative genes have been identified in mouse models for most of the syndromic recessive ciliopathies described above, as well as non-syndromic cilia-related disorders, such as polycystic kidney diseases and degenerative retinopathies. 50 Study of these relevant models, both in terms of whole animals and derived cells, has allowed a much deeper understanding of the cell biology that underlies the different progressive stages and manifestations of the disease, as well as providing a key resource for the testing of novel therapeutic approaches.…”