Configuring a robust nervous system with Fat cadherins

Abstract

Atypical Fat cadherins represent a small but versatile group of signaling molecules that influence proliferation and tissue polarity. With huge extracellular domains and intracellular domains harboring many independent protein interaction sites, Fat cadherins are poised to translate local cell adhesion events into a variety of cell behaviors. The need for such global coordination is particularly prominent in the nervous system, where millions of morphologically diverse neurons are organized into functional networks. As we learn more about their biological functions and molecular properties, increasing evidence suggests that Fat cadherins mediate contact-induced changes that ultimately impose a structure to developing neuronal circuits.

Keywords: Fat cadherins; Fat-like cadherins; Neural development; Planar polarity; Tissue polarity.

Figure 1. Fat cadherin signaling

(A) In flies, Ft binds to Ds, and the strength of this interaction is regulated by phosphorylation by the Golgi kinase Fj. Ft binds intracellularly to Discs overgrown (Dco), Lowfat, Fbxl7, Dlish/Vamana and Atrophin (Atro) and its activity is regulated by Approximated (App). Ft/Ds interactions lead to asymmetric distribution of the myosin Dachs, activation of the Hippo pathway and consequently the control of proliferation and tissue polarity. There is no known ligand for Fat-like. However, it signals through binding to the WAVE regulatory complex (WRC) to promote cytoskeleton rearrangements. (B) In flies, the Ft/Ds system is activated along a gradient, extending along the proximal (Px)-distal (Dt) axis of the wing or from the poles (Pl) to the equator (Eq) of the eye. Ft is uniformly expressed, with Ds and Fj in opposing gradients. The resulting gradient of Ft activity results in asymmetric localization of Dachs (D) and hence polarized alignment of cells along this gradient. (C) In vertebrates, the Ft ortholog Fat4 binds to the Ds ortholog Dchs1. Intracellularly, Fat4 binds to the MUPP1-Pals1 complex, and possibly to Atrophin1 and Atrophin 2L (Atn1/2L). Fat2 mediates homophilic interactions, whereas the ligands for Fat1 and Fat3 remain to be elucidated. Fat1 binds to a variety of intracellular molecules, including cytoskeletal regulators such as Ena/VASP, Homer1 and Homer3, and probably WRC, as well as the Atn transcriptional regulators. Fat3 binds to WRC and Ena/VASP. How any of these interactions actually influence polarity remains unclear.

Figure 2. Fat cadherins influence multiple features of neuronal development

(A) In wild-type (WT) animals, the cochlea contains one row of inner hair cells (IHC) and three rows of outer hair cells (OHC1-3), each with a single kinocilium (green) asymmetrically positioned at the edge of the apical surface, adjacent to a polarized bundle of actin-rich stereocilia (red). In fat4 mutants, HCs are mildly misaligned and an extra fourth row of OHCs appears in some cochlear turns. fat4 synergizes with fat1, whereas loss of fat3 suppresses the fat4 phenotype. (B) During development of the WT retina, amacrine cell precursors (green) migrate through the neuroblast layer (NBL) to the inner nuclear layer (INL) and the ganglion cell layer (GCL), gradually acquiring a unipolar morphology with one primary dendrite extending into the inner plexiform layer (IPL). fat3 mutant amacrine cell precursors vacillate as they travel toward the IPL and then often retain neurites outside of the IPL, exhibiting a bipolar shape in the mature retina. OLM: outer limiting membrane, ONL: outer nuclear layer, OPL: outer plexiform layer. (C) In the WT neocortex, neuroepithelial cells (purple) proliferate in the ventricular zone (VZ) and give rise to neurons (yellow) that migrate along the radial glia to the cortical plate (CP), where they differentiate. Within the ventricular zone, the progenitors form Fat4/Dchs1-positive “subapical membrane appositions” (SAMA) just apical to the adherens junctions (AJ). Depletion of either fat1 or fat4 induces overproliferation of neuronal precursors and accumulation of differentiated neurons below the CP, accompanied by disruptions in the SAMA. SVZ: subventricular zone, IZ: intermediate zone, MZ: marginal zone.