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

Abstract

Mammalian brain development requires coordination between neural precursor proliferation, differentiation and cellular organization to create the intricate neuronal networks of the adult brain. Here, we examined the role of the atypical cadherins Fat1 and Fat4 in this process. We show that mutation of Fat1 in mouse embryos causes defects in cranial neural tube closure, accompanied by an increase in the proliferation of cortical precursors and altered apical junctions, with perturbations in apical constriction and actin accumulation. Similarly, knockdown of Fat1 in cortical precursors by in utero electroporation leads to overproliferation of radial glial precursors. Fat1 interacts genetically with the related cadherin Fat4 to regulate these processes. Proteomic analysis reveals that Fat1 and Fat4 bind different sets of actin-regulating and junctional proteins. In vitro data suggest that Fat1 and Fat4 form cis-heterodimers, providing a mechanism for bringing together their diverse interactors. We propose a model in which Fat1 and Fat4 binding coordinates distinct pathways at apical junctions to regulate neural progenitor proliferation, neural tube closure and apical constriction.

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

“…Gene inactivation of either Fat4 or Dchs1 in mice results in a wide spectrum of phenotypes ranging from branching and cystic defects in the kidney, altered neuronal proliferation and migration, to a change in sternum shape (Saburi et al, 2008(Saburi et al, , 2012Mao et al, 2011Mao et al, , 2015Mao et al, , 2016Zakaria et al, 2014;Bagherie-Lachidan et al, 2015;Badouel et al, 2015). FAT4 and DCHS1 are also essential in humans, and compound mutations result in Van Maldergem syndrome, which is characterised, in part, by intellectual disability and altered craniofacial development (Cappello et al, 2013); in some individuals vertebral defects have also been reported (Mansour et al, 2012).…”

A next-generation microarray further reveals stage-enriched gene expression pattern in the blood fluke Schistosoma japonicum

“…The over-expression of the top 25 genes in hepatic schistosomula appears to reflect a diversity of physiological activities, including transcriptional (homeobox protein engrailed-like SMOX-2 [47, 48], serum and glucocorticoid-regulated kinase 1 (SGK1) [49] and nuclear receptor subfamily 4 group A [50, 51]) and neuronal (protocadherin FAT4 [52], Aromatic-L-amino-acid decarboxylase [53] and delphilin [54]) activities, together with tegumental integrity (annexin A3 [55, 56]), skeletal morphogenesis (protocadherin FAT4 [57]) and endosome-to-Golgi retrieval (vacuolar protein sorting-associated protein 29 [58]).…”

Fat-like cadherins in cell migration—leading from both the front and the back

“…For example, it is not yet known whether Fat1 functions at the leading edge or trailing edge during myoblast migration in mice [21]. Moreover, because the Fat cadherins have overlapping functions in some mammalian tissues [47,48], careful analysis of double and triple knockouts may be required to identify all of the cell migratory events that are guided by these proteins.…”