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Dis Model Mech. 2011 January; 4(1): 54.
PMCID: PMC3014344

TRANSLATIONAL IMPACT

Clinical issue

Meckel-Gruber syndrome (MKS) is a lethal recessive disorder with multiple severe birth defects, including polycystic kidneys, polydactyly, cleft lip and palate, skeletal anomalies, laterality defects, and congenital heart malformations. MKS is considered a ciliopathy, because five of the six genes associated with MKS are known to be required for ciliogenesis. However, the exact nature of the ciliary defect in MKS is unclear. Cilia serve diverse biological functions, which include cell motility, generating fluid flow and mediating sensory functions such as detection of light, odorants, protein ligands and other chemicals, as well as regulating mechanosensation in shear stress and flow sensing. During development, motile cilia at the embryonic node generate directional fluid flow, which, together with primary (non-motile) cilia at the node periphery, propagates signals that establish the left-right body axis. Primary cilia also have other important functions during development, such as the transduction of sonic hedgehog (Shh) signaling and planar-cell-polarity (PCP) signaling or non-canonical Wnt signaling. Defects in the diverse functions of motile and non-motile cilia might account for the broad spectrum of developmental malformations observed in MKS patients.

Results

The authors characterize a mouse mutant recovered from an ENU screen that has a constellation of defects that resemble the symptoms observed in MKS patients. In the kidneys of mutant mice, glomerular and tubule cysts are observed, together with short and near complete loss of the cilia. Underlying the left-right patterning defects are fewer and shorter nodal cilia with no directional flow. In the cochlea, the stereocilia are mal-patterned, with the kinocilia abnormally positioned. Together, these defects suggest a disruption in PCP signaling pathways that are known to regulate node, kidney and cochlea development. The authors also show that Shh signaling is disrupted in the neural tube and limb bud of the mutant mice, which underlies preaxial digit duplication. The mutation in these mice maps to Mks1, which encodes a protein that localizes to the centrosome (a structure composed of microtubule-based centrioles that is central for ciliogenesis). The mutation disrupts the highly conserved B9 domain of Mks1, which is also found in two other centrosome proteins. The mutant protein no longer localizes to the centrosome, suggesting that the B9 domain plays a role in centrosomal targeting. In Mks1-mutant mouse embryonic fibroblasts and kidney epithelia, centrosomes are formed but ciliogenesis is severely disrupted. These findings indicate that the localization of Mks1 to the centrosome is required for ciliogenesis of motile and non-motile cilia, but not for centrosome assembly.

Implications and future directions

This work demonstrates that Mks1 is a centrosomal protein that is required for ciliogenesis, and provides new insights into the molecular events that underlie the wide range of birth defects associated with MKS. Important future studies will include examining the role of the B9 domain in targeting Mks1 to the centrosomes and the role that this plays in ciliogenesis. These findings also emphasize the value of mutagenesis screens for identifying disease-associated genes.


Articles from Disease Models & Mechanisms are provided here courtesy of Company of Biologists