Astrocyte-intrinsic and -extrinsic Fat1 activities regulate astrocyte development and angiogenesis in the retina.

Angiogenesis is a stepwise process leading to blood vessel formation. In the vertebrate retina, endothelial cells are guided by astrocytes migrating along the inner surface, and the two processes are coupled by a tightly regulated cross-talks between the two cell types. Here, I have investigated how the FAT1 cadherin, a regulator of tissue morphogenesis that governs tissue cross-talk, influences retinal vascular development. Late-onset Fat1 inactivation in the neural lineage in mice, by interfering with astrocyte progenitor migration polarity and maturation, delayed postnatal retinal angiogenesis, leading to persistent vascular abnormalities in adult retinas. Impaired astrocyte migration and polarity were not associated with alterations of retinal ganglion cell axonal trajectories or of the inner limiting membrane. In contrast, inducible Fat1 ablation in postnatal astrocytes was sufficient to alter their migration polarity and proliferation. Altogether, this study uncovers astrocyte-intrinsic and -extrinsic Fat1 activities that influence astrocyte migration polarity, proliferation and maturation, disruption of which impacts retinal vascular development and maintenance.

Configuring a robust nervous system with Fat cadherins.

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.

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

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.

Sleeping giants: emerging roles for the fat cadherins in health and disease.

The vertebrate Fat cadherins comprise a small gene family of four members, Fat1-Fat4, all closely related in structure to Drosophila ft and ft2. Over the past decade, knock-out mouse studies, genetic manipulation, and large sequencing projects has aided our understanding of the function of vertebrate Fat cadherins in tissue development and disease. The majority of studies of this family have focused on Fat1, with evidence now showing it can bind enable (ENA)/Vasodilator-stimulated phosphoprotein (VASP), ß-catenin and Atrophin proteins to influence cell polarity and motility; HOMER-1 and HOMER-3 proteins to regulate actin accumulation in neuronal synapses; and scribble to influence the Hippo signaling pathway. Fat2 and Fat3 can regulate cell migration in a tissue specific manner and Fat4 appears to influence both planar cell polarity and Hippo signaling recapitulating the activity of Drosophila ft. Knowledge about the exact downstream signaling pathways activated by each family member remains in its infancy, but it is becoming clearer that they have tissue specific and redundant roles in development and may be lost or gained in cancer. In this review, we summarize the recent progress on understanding the role of the Fat cadherin family, integrating the current knowledge of molecular interactions and tissue distributions, together with the accumulating evidence of their changed expression in human disease. The latter is now beginning to promote interest in these molecules as both biomarkers and new targets for therapeutic intervention.

High temporal frequency light response in mouse retina is mediated by ON and OFF bipolar cells and requires FAT3 signaling.

Vision is initiated by the reception of light by photoreceptors and subsequent processing via parallel retinal circuits. Proper circuit organization depends on the multi-functional tissue polarity protein FAT3, which is required for amacrine cell connectivity and retinal lamination. Here we investigated the retinal function of Fat3 mutant mice and found decreases in physiological and perceptual responses to high frequency flashes. These defects did not correlate with abnormal amacrine cell wiring, pointing instead to a role in bipolar cell subtypes that also express FAT3. Indeed, similar deficits were observed in mice lacking the bipolar cell glutamate receptors GRIK1 (OFF-bipolar cells) and GRM6 (ON-bipolar cells). Mechanistically, FAT3 binds to the synaptic protein PTPσ and is required to localize GRIK1 to OFF-cone bipolar cell synapses with cone photoreceptors. How FAT3 impacts ON-cone bipolar cell function at high temporal frequency remains to be uncovered. These findings expand the repertoire of FAT3's functions and reveal the importance of both ON- and OFF-bipolar cells for high frequency light response.

Fat and Dachsous cadherins in mammalian development.

Cell growth and patterning are critical for tissue development. Here we discuss the evolutionarily conserved cadherins, Fat and Dachsous, and the roles they play during mammalian tissue development and disease. In Drosophila, Fat and Dachsous regulate tissue growth via the Hippo pathway and planar cell polarity (PCP). The Drosophila wing has been an ideal tissue to observe how mutations in these cadherins affect tissue development. In mammals, there are multiple Fat and Dachsous cadherins, which are expressed in many tissues, but mutations in these cadherins that affect growth and tissue organization are context dependent. Here we examine how mutations in the Fat and Dachsous mammalian genes affect development in mammals and contribute to human disease.

Fat3 acts through independent cytoskeletal effectors to coordinate asymmetric cell behaviors during polarized circuit assembly.

The polarized flow of information through neural circuits depends on the orderly arrangement of neurons, their processes, and their synapses. This polarity emerges sequentially in development, starting with the directed migration of neuronal precursors, which subsequently elaborate neurites that form synapses in specific locations. In other organs, Fat cadherins sense the position and then polarize individual cells by inducing localized changes in the cytoskeleton that are coordinated across the tissue. Here, we show that the Fat-related protein Fat3 plays an analogous role during the assembly of polarized circuits in the murine retina. We find that the Fat3 intracellular domain (ICD) binds to cytoskeletal regulators and synaptic proteins, with discrete motifs required for amacrine cell migration and neurite retraction. Moreover, upon ICD deletion, extra neurites form but do not make ectopic synapses, suggesting that Fat3 independently regulates synapse localization. Thus, Fat3 serves as a molecular node to coordinate asymmetric cell behaviors across development.

Role of FAT1 in health and disease.

FAT atypical cadherin 1 (FAT1), which encodes a protocadherin, is one of the most frequently mutated genes in human cancer. Over the past 20 years, the role of FAT1 in tissue growth and in the development of diseases has been extensively studied. There is definitive evidence that FAT1 serves a substantial role in the maintenance of organs and development, and its expression appears to be tissue-specific. FAT1 activates a variety of signaling pathways through protein-protein interactions, including the Wnt/ß-catenin, Hippo and MAPK/ERK signaling pathways, which affect cell proliferation, migration and invasion. Abnormal FAT1 expression may lead to the development of tumors and may affect prognosis. Therefore, FAT1 may have potential in tumor therapy. The structural and functional changes mediated by FAT1, its tissue distribution and changes in FAT1 expression in human diseases are described in the present review, which provides further insight for understanding the role of FAT1 in development and disease.

History and progression of Fat cadherins in health and disease.

Intercellular adhesions are vital hubs for signaling pathways during multicellular development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases. As a member of the Ca2+-dependent adhesion super-family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure. Functionally, FAT1 was found to regulate cell migration and growth control through specific protein-protein interactions of its cytoplasmic tail. FAT2 and FAT3 are relatively less studied and are thought to participate in the development of human cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has been widely studied in the context of biological functions and tumor mechanisms and has been shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as emerging disease biomarkers and as novel therapeutic targets.