Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development

Abstract

SUMMARYThe Drosophila Dachsous and Fat proteins function as ligand and receptor, respectively, for an intercellular signaling pathway that regulates Hippo signaling and planar cell polarity. Although gene-targeted mutations in two mammalian Fat genes have been described, whether mammals have a Fat signaling pathway equivalent to that in Drosophila, and what its biological functions might be, have remained unclear. Here, we describe a gene-targeted mutation in a murine Dachsous homolog, Dchs1. Analysis of the phenotypes of Dchs1 mutant mice and comparisons with Fat4 mutant mice identify requirements for these genes in multiple organs, including the ear, kidney, skeleton, intestine, heart and lung. Dchs1 and Fat4 single mutants and Dchs1 Fat4 double mutants have similar phenotypes throughout the body. In some cases, these phenotypes suggest that Dchs1-Fat4 signaling influences planar cell polarity. In addition to the appearance of cysts in newborn kidneys, we also identify and characterize a requirement for Dchs1 and Fat4 in growth, branching and cell survival during early kidney development. Dchs1 and Fat4 are predominantly expressed in mesenchymal cells in multiple organs, and mutation of either gene increases protein staining for the other. Our analysis implies that Dchs1 and Fat4 function as a ligand-receptor pair during murine development, and identifies novel requirements for Dchs1-Fat4 signaling in multiple organs.

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

“…Interestingly, genetic epistasis experiments showed that Merlin cooperates with Expanded to activate the Hippo pathway in the fly [32]. Mammalian cells lack a clear functional homologue of Fat [87,88]. A recent study suggested that the FERM6/Willin pro- [87,88].…”

“…Mammalian cells lack a clear functional homologue of Fat [87,88]. A recent study suggested that the FERM6/Willin pro- [87,88]. A recent study suggested that the FERM6/Willin pro-.…”

Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

“…Embryos mutant for Fat4 exhibit PCP defects, suggesting that the polarity function of Fat is conserved (Saburi et al, 2008;Mao et al, 2011). The Fat4 intracellular domain can rescue most of the PCP defects of fat mutant flies (Pan et al, 2013).…”

Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP

“…The mammalian orthologues of Mer (also called NF2, Mer) and Kibra have been shown to function as upstream members of the Hippo pathway, but the identity of other upstream members of the mammalian Hippo pathway has remained enigmatic. For example, recent studies suggest that the Fat/Dachsous pathway does not control organ size and activity of the Yki orthologues, YAP and TAZ, in mice (Saburi et al, 2008;Mao et al, 2011). Interestingly, repression of YAP by AMOT via direct interaction of the WW domains of YAP with the PPXY motifs of AMOT has been reported (Zhao et al, 2011), a role fulfilled by the C terminus of Ex in D. melanogaster.…”