Mks6 mutations reveal tissue‐ and cell type‐specific roles for the cilia transition zone

Abstract

The transition zone (TZ) is a domain at the base of the cilium that is involved in maintaining ciliary compartment-specific sensory and signaling activity by regulating cilia protein composition. Mutations in TZ proteins result in cilia dysfunction, often causing pleiotropic effects observed in a group of human diseases classified as ciliopathies. The purpose of this study is to describe the importance of the TZ component Meckel-Grüber syndrome 6 ( Mks6) in several organ systems and tissues regarding ciliogenesis and cilia maintenance using congenital and conditional mutant mouse models. Similar to MKS, congenital loss of Mks6 is embryonic lethal, displaying cilia loss and altered cytoskeletal microtubule modifications but only in specific cell types. Conditional Mks6 mutants have a variable cystic kidney phenotype along with severe retinal degeneration with mislocalization of phototransduction cascade proteins. However, other phenotypes, such as anosmia and obesity, which are typically associated with cilia and TZ dysfunction, were not evident. These data indicate that despite Mks6 being a core TZ component, it has tissue- or cell type-specific functions important for cilia formation and cilia sensory and signaling activities. Lewis, W. R., Bales, K. L., Revell, D. Z., Croyle, M. J., Engle, S. E., Song, C. J., Malarkey, E. B., Uytingco, C. R., Shan, D., Antonellis, P. J., Nagy, T. R., Kesterson, R. A., Mrug, M. M., Martens, J. R., Berbari, N. F., Gross, A. K., Yoder, B. K. Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone.

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…Mice with null mutations in Cc2d2a experience embryonic lethality due to the absence of subdistal appendages and nodal cilia [88]. The retinas of adult mice with tamoxifen-induced deletion of Cc2d2a in PRs have a significantly diminished ONL (2-3 layers) 12 weeks post-injection [92], suggesting that CC2D2A is necessary for ciliary homeostasis.…”

Rpgrip1l controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone

“…However, loss of Nphp1, Nphp4 and Invs did not alter the ciliary amount of Arl13b or Sstr3 in MEFs and NIH3T3 cells ( Figure 1B and Figure 2) indicating that they are not involved in gating these proteins in vertebrate primary cilia. Remarkably, several reports point to cell type-specific functions of some TZ proteins [14,16,27,41,42] making a potential regulation of ciliary gating by Nphp1, Nphp4 and Invs in other vertebrate cell types conceivable. Rpgrip1l -/and Cep290 -/mice have a much more severe phenotype than Nphp1 -/-, Nphp4 -/and Invs -/mice [20,25,27,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59].…”

“…For this reason, the assembly and function of the TZ is a hot topic in biomedical research. A lot of proteins participate in TZ assembly and/or function as ciliary gatekeepers at the TZ [12- 14,16,17,19,23,24,27,29,30,33,34,37,41,69,70,[73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90]. However, the relationships between these proteins and hence the mechanisms underlying ciliary gating at the TZ remain largely elusive.…”

“…Proteins were detected with secondary antibodies conjugated to horseradish peroxidase (RPN4201 and RPN4301) and the ECL detection kit (both GE Healthcare). Visualization of 16 protein bands was realized by LAS-4000 mini (Fujifilm). Band intensities were measured by using ImageJ (National Institutes of Health).…”

“…In many cases, ciliopathies are caused by mutations in genes encoding TZ proteins [3,4]. As the TZ functions as the ciliary gatekeeper governing ciliary protein import and export [4][5][6][7][8][9][10][11][12], a defective TZ can affect the proper formation of cilia and alter signalling pathways transduction [13][14][15][16][17][18][19][20][21][22][23][24]. Thus, the investigation of the molecular mechanisms underlying TZ function is an important prerequisite for the development of curative ciliopathy therapies.…”