Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

Abstract

The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4 −/− and Dchs1 −/− mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae.

The novel SH3 domain protein Dlish/CG10933 mediates fat signaling in Drosophila by binding and regulating Dachs

“…Mutations in Fat’s closest mammalian homolog Fat4 (FatJ) and its Ds-like ligands strongly disrupt PCP-like processes, and have in humans been associated with the multisystem defects of Hennekam and Van Maldergem syndromes ( Alders et al, 2014 ; Mao et al, 2011 ; Saburi et al, 2008 ; Zakaria et al, 2014 ). There has been some debate, however, about whether the mammalian proteins retain direct regulation of Hippo activity ( Bagherie-Lachidan et al, 2015 ; Bossuyt et al, 2014 ; Pan et al, 2013 ; Sadeqzadeh et al, 2014 ; Kuta et al, 2016 ). Nonetheless, Fat4 has been linked to Hippo changes in both normal development and tumors ( Qi et al, 2009 ; Van Hateren et al, 2011 ), mutations in Fat4 or Dachsous1 change the balance of precursors and mature neurons in the developing neuroepithelium of both humans and mice, and the mouse defect can be reversed by knockdown of the Yki homolog Yap ( Cappello et al, 2013 ).…”

Dchs1-Fat4 regulation of osteogenic differentiation in mouse

“…The increased proliferation within the osteogenic progenitors is analogous to the role of Dchs1-Fat4 signalling in the cerebral cortex and heart (Cappello et al, 2013;Ragni et al, 2017) and in contrast to the decreased proliferation observed in the kidney and somites (Kuta et al, 2016;Mao et al, 2011). As in the heart and brain, loss of Dchs1-Fat4 signalling also resulted in increased Yap activity.…”

Comparing atmospheric and hypoxic cultured mesenchymal stem cell transcriptome: implication for stem cell therapies targeting intervertebral discs

“…Dachsous cadherin-related 1 (DCHS1) expression is up regulated in hypoxic conditions by fivefold and is a cellular adhesion molecule member of the cadherin superfamily. Lack of DCHS1 results in developmental defects of the early sclerotome associated with fewer chondrogenic cells within the developing vertebral body [ 35 ]. Keratin 19 (KRT19) expression showed a fourfold increase in hypoxic cultured samples and is an intermediate filament protein that is part of the keratin family.…”