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Loss of Fat1 leads to cranial neural tube defects. (A) Schematic of mouse cortex development. Radial precursors are bipolar cells that can divide symmetrically to self-renew, or asymmetrically, producing either an intermediate neuronal progenitor, or a neuron that can migrate along radial precursor basal processes to form the new neuronal layers of the cortex. (B) Fat1 expression in a coronal section from E13.5 brain revealed by in situ hybridization. The left panel is a magnification of the cortex. Note that Fat1 is strongly expressed in the VZ of the cortex containing radial precursors. (C) Coronal section through E14.5 Fat1 +/− brain stained for β-galactosidase to assess Fat1-lacZ expression. (D) Coronal section through E14.5 brain stained for β-galactosidase (red) and the cortical precursor marker Pax6 (green) and with Hoechst (blue). (E) Dorso-anterior view of an E11.5 Fat1 −/− embryo and a control sibling. Note that anterior neural folds are open in Fat1 −/− (arrow). (F) E13.5 Fat1 −/− embryo showing exencephaly and control sibling. VZ, ventricular zone; SVZ, subventricular zone; IZ, intermediate zone; CP, cortical plate; V, ventricle. Scale bars: 100 µm in B; 500 µm in C; 40 µm in D.
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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 have 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 cr...
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... cells with apical adherens junctions that line the lateral ventricle, forming an epithelial structure. These radial precursors can divide symmetrically or asymmetrically, producing either an intermediate neuronal progenitor, or a neuron that can then migrate along the radial precursor basal process to form the new neuronal layers of the cortex (Fig. ...
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... is present in the developing central nervous system with strong expression in the neocortex ( Ciani et al., 2003). We analyzed in detail Fat1 expression in the developing cortex throughout neurogenesis from E11.5 to E18.5 ( Fig. 1B,C; supplementary material Fig. S1A-C). Interestingly, this analysis revealed that Fat1 expression is strongest in the germinal region known as the ventricular and subventricular zone (VZ and SVZ) of the developing cortex at mid-neurogenesis (E13-14) (Fig. 1B,C; supplementary material Fig. S1B). Towards the end of neurogenesis, at E18.5, ...
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... is present in the developing central nervous system with strong expression in the neocortex ( Ciani et al., 2003). We analyzed in detail Fat1 expression in the developing cortex throughout neurogenesis from E11.5 to E18.5 ( Fig. 1B,C; supplementary material Fig. S1A-C). Interestingly, this analysis revealed that Fat1 expression is strongest in the germinal region known as the ventricular and subventricular zone (VZ and SVZ) of the developing cortex at mid-neurogenesis (E13-14) (Fig. 1B,C; supplementary material Fig. S1B). Towards the end of neurogenesis, at E18.5, Fat1 expression can also be seen in ...
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... Fat1 expression in the developing cortex throughout neurogenesis from E11.5 to E18.5 ( Fig. 1B,C; supplementary material Fig. S1A-C). Interestingly, this analysis revealed that Fat1 expression is strongest in the germinal region known as the ventricular and subventricular zone (VZ and SVZ) of the developing cortex at mid-neurogenesis (E13-14) (Fig. 1B,C; supplementary material Fig. S1B). Towards the end of neurogenesis, at E18.5, Fat1 expression can also be seen in the upper neuronal layer of the cortex (supplementary material Fig. S1C). Taking advantage of Fat1-lacZ mice, we performed β-galactosidase staining to show that Fat1 expression colocalizes strongly with the radial precursor ...
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... cortex throughout neurogenesis from E11.5 to E18.5 ( Fig. 1B,C; supplementary material Fig. S1A-C). Interestingly, this analysis revealed that Fat1 expression is strongest in the germinal region known as the ventricular and subventricular zone (VZ and SVZ) of the developing cortex at mid-neurogenesis (E13-14) (Fig. 1B,C; supplementary material Fig. S1B). Towards the end of neurogenesis, at E18.5, Fat1 expression can also be seen in the upper neuronal layer of the cortex (supplementary material Fig. S1C). Taking advantage of Fat1-lacZ mice, we performed β-galactosidase staining to show that Fat1 expression colocalizes strongly with the radial precursor markers Pax6 and nestin in the ...
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... is strongest in the germinal region known as the ventricular and subventricular zone (VZ and SVZ) of the developing cortex at mid-neurogenesis (E13-14) (Fig. 1B,C; supplementary material Fig. S1B). Towards the end of neurogenesis, at E18.5, Fat1 expression can also be seen in the upper neuronal layer of the cortex (supplementary material Fig. S1C). Taking advantage of Fat1-lacZ mice, we performed β-galactosidase staining to show that Fat1 expression colocalizes strongly with the radial precursor markers Pax6 and nestin in the neocortex ( Fig. 1D; supplementary material Fig. S1D). This expression pattern suggests that Fat1 is involved in cortical development, possibly regulating ...
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... Towards the end of neurogenesis, at E18.5, Fat1 expression can also be seen in the upper neuronal layer of the cortex (supplementary material Fig. S1C). Taking advantage of Fat1-lacZ mice, we performed β-galactosidase staining to show that Fat1 expression colocalizes strongly with the radial precursor markers Pax6 and nestin in the neocortex ( Fig. 1D; supplementary material Fig. S1D). This expression pattern suggests that Fat1 is involved in cortical development, possibly regulating cortical ...
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... at E18.5, Fat1 expression can also be seen in the upper neuronal layer of the cortex (supplementary material Fig. S1C). Taking advantage of Fat1-lacZ mice, we performed β-galactosidase staining to show that Fat1 expression colocalizes strongly with the radial precursor markers Pax6 and nestin in the neocortex ( Fig. 1D; supplementary material Fig. S1D). This expression pattern suggests that Fat1 is involved in cortical development, possibly regulating cortical ...
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... elucidate the role of Fat1 in cortical development, we analyzed Fat1 mutant embryos. Neural tube closure normally concludes at ∼E10 with cranial fold and caudal neuropore closure. At E11.5, we find that ∼40% (6/17) of Fat1 −/− embryos in a CD-1 genetic background show open and separated anterior neural folds (Fig. 1E). This defect is specific to the cranial region, since Fat1 −/− embryos have a closed posterior neural tube. Cranial NTDs lead to exencephaly, characterized by an expansion of the brain outside the skull, which is visible as early as E13-14 ( Fig. 1F). At E14.5, ∼40% (16/37) of CD-1 Fat1 −/− embryos are ...
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... of Fat1 −/− embryos in a CD-1 genetic background show open and separated anterior neural folds (Fig. 1E). This defect is specific to the cranial region, since Fat1 −/− embryos have a closed posterior neural tube. Cranial NTDs lead to exencephaly, characterized by an expansion of the brain outside the skull, which is visible as early as E13-14 ( Fig. 1F). At E14.5, ∼40% (16/37) of CD-1 Fat1 −/− embryos are ...
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... at mid-neurogenesis (E14-15), when defects in proliferation and differentiation of cortical precursors can be easily assessed. Development of the mouse cortex follows a well-established pattern: radial precursors line the lateral ventricles and form the VZ, and can give rise to more radial precursors, neurons or intermediate neuronal progenitors (Fig. 1A). Above the VZ, intermediate neuronal progenitors divide away from the ventricular surface and populate the SVZ to eventually produce neurons ( Englund et al., 2005). Newborn neurons migrate through the intermediate zone (IZ) to form the neuronal layers of the cortical plate ...
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... −/− exencephalic brains was analyzed by staining coronal sections for the dorsal cortical precursor marker Pax6, the pan-neuronal marker βIII-tubulin, the intermediate neuronal progenitor marker Tbr2 (Eomes -Mouse Genome Informatics), the layer 2-4 neuronal marker Satb2 and the ventral interneuron marker Dlx2 ( Fig. 2A; supplementary material Fig. S1E,F). This analysis revealed that the third ventricle is open in Fat1 −/− exencephalic brains and that the thalamic region is expanded to the point of being displaced on top of the cortical hemispheres ( Fig. 2A; supplementary material Fig. S1E,F). In contrast to the 'exposed' third ventricle of the thalamus, both the lateral ventricles of ...
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... -Mouse Genome Informatics), the layer 2-4 neuronal marker Satb2 and the ventral interneuron marker Dlx2 ( Fig. 2A; supplementary material Fig. S1E,F). This analysis revealed that the third ventricle is open in Fat1 −/− exencephalic brains and that the thalamic region is expanded to the point of being displaced on top of the cortical hemispheres ( Fig. 2A; supplementary material Fig. S1E,F). In contrast to the 'exposed' third ventricle of the thalamus, both the lateral ventricles of the cortex are present and appear closed. However, coronal cortical sections stained for Pax6 and Tbr2 revealed a dramatic lateral expansion of the VZ (Fig. 2A). Lateral ventricle length was quantified by measuring the length of the apical VZ ...
Citations
... Fz5/8 is a non-canonical Wnt PCP pathway receptor that is necessary for primary invagination and archenteron formation [57][58][59][60], possibly through its activation of RhoA [58] or Dishevelled [59] and downstream effects on Jun-N-terminal kinase activity [60]. While studies suggest that the molecular relationship between the Fat-DCHS and non-canonical Wnt pathways depends on the organism and tissue [30,61], Fat and DCHS orthologs have been demonstrated to be necessary for cytoskeleton-mediated epithelial tissue remodeling [9,30,34,[61][62][63]. Some examples of this remodeling include endomesoderm convergent-extension movements during zebrafish gastrulation [62] and apical constriction during mammalian neurulation [63], which involve mechanical processes that also occur during sea urchin gastrulation [20][21][22]58]. ...
... While studies suggest that the molecular relationship between the Fat-DCHS and non-canonical Wnt pathways depends on the organism and tissue [30,61], Fat and DCHS orthologs have been demonstrated to be necessary for cytoskeleton-mediated epithelial tissue remodeling [9,30,34,[61][62][63]. Some examples of this remodeling include endomesoderm convergent-extension movements during zebrafish gastrulation [62] and apical constriction during mammalian neurulation [63], which involve mechanical processes that also occur during sea urchin gastrulation [20][21][22]58]. Echinoderm Fat1, Fat4, and DCHS2 may also contribute to development of the archenteron into the larval tripartite gut because their expression patterns resolve to boundaries demarcated by the cardiac and pyloric sphincters after gastrulation [64]. ...
... Fat1, Fat4, DCHS2, and PCDH9 may also be involved in the neurogenesis of the apical organ and ciliary band. Vertebrate Fat1, Fat4, and DCHS2 orthologs serve essential functions in regulating neuron migration, proliferation and shape [63,[65][66][67], such as inducing neurite outgrowth by antagonizing Hippo effectors [65,66], enabling coordinated cell migration of different neuronal subtypes [67], and forming heterodimeric complexes that regulate neuroepithelial remodeling [63]. Based on previous vertebrate studies, PCDH9 may function as a tumor suppressor in echinoderm neuroectodermal tissues [40,45,68,69]. ...
Background
Cadherins are calcium-dependent transmembrane cell–cell adhesion proteins that are essential for metazoan development. They consist of three subfamilies: classical cadherins, which bind catenin, protocadherins, which contain 6–7 calcium-binding repeat domains, and atypical cadherins. Their functions include forming adherens junctions, establishing planar cell polarity (PCP), and regulating cell shape, proliferation, and migration. Because they are basal deuterostomes, echinoderms provide important insights into bilaterian evolution, but their only well-characterized cadherin is G-cadherin, a classical cadherin that is expressed by many embryonic epithelia. We aimed to better characterize echinoderm cadherins by conducting phylogenetic analyses and examining the spatiotemporal expression patterns of cadherin-encoding genes during Strongylocentrotus purpuratus development.
Results
Our phylogenetic analyses conducted on two echinoid, three asteroid, and one crinoid species identified ten echinoderm cadherins, including one deuterostome-specific ortholog, cadherin-23, and an echinoderm-specific atypical cadherin that possibly arose in an echinoid-asteroid ancestor. Catenin-binding domains in dachsous-2 orthologs were found to be a deuterostome-specific innovation that was selectively lost in mouse, while those in Fat4 orthologs appeared to be Ambulacraria-specific and were selectively lost in non-crinoid echinoderms. The identified suite of echinoderm cadherins lacks vertebrate-specific innovations but contains two proteins that are present in protostomes and absent from mouse. The spatiotemporal expression patterns of four embryonically expressed cadherins (fat atypical cadherins 1 and 4, dachsous-2, and protocadherin-9) were dynamic and mirrored the expression pattern of Frizzled 5/8, a non-canonical Wnt PCP pathway receptor protein essential for archenteron morphogenesis.
Conclusions
The echinoderm cadherin toolkit is more similar to that of an ancient bilaterian predating protostomes and deuterostomes than it is to the suite of cadherins found in extant vertebrates. However, it also appears that deuterostomes underwent several cadherin-related innovations. Based on their similar spatiotemporal expression patterns and orthologous relationships to PCP-related and tumor-suppressing proteins, we hypothesize that sea urchin cadherins may play a role in regulating the shape and growth of embryonic epithelia and organs. Future experiments will examine cadherin expression in non-echinoid echinoderms and explore the functions of cadherins during echinoderm development.
... In contrast, one RGC gene, PSAP, was induced by dSMADi. The atypical cadherin FAT1 controls RGC proliferation, and its loss leads to abnormal radial glia morphology and neural tube defects (Badouel et al., 2015). We found that FAT1 was strongly expressed by neural rosettes ( Figure S1E and S1F). ...
Human gliogenesis remains poorly understood, and derivation of astrocytes from human pluripotent stem cells (hPSCs) is inefficient and cumbersome. Here, we report controlled glial differentiation from hPSCs that bypasses neurogenesis, which otherwise precedes astrogliogenesis during brain development and in vitro differentiation. hPSCs were first differentiated into radial glial cells (RGCs) resembling resident RGCs of the fetal telencephalon, and modulation of specific cell signaling pathways resulted in direct and stepwise induction of key astroglial markers (NFIA, NFIB, SOX9, CD44, S100B, glial fibrillary acidic protein [GFAP]). Transcriptomic and genome-wide epigenetic mapping and single-cell analysis confirmed RGC-to-astrocyte differentiation, obviating neurogenesis and the gliogenic switch. Detailed molecular and cellular characterization experiments uncovered new mechanisms and markers for human RGCs and astrocytes. In summary, establishment of a glia-exclusive neural lineage progression model serves as a unique serum-free platform of manufacturing large numbers of RGCs and astrocytes for neuroscience, disease modeling (e.g., Alexander disease), and regenerative medicine.
... Notably, FAT1 knockdown in epithelial cells impaired migration in a scratch-wound assay, and this was associated with deficient lamellipodia formation and the loss of cell polarity [25]. Interestingly, in the process of neural tube closure during mouse development, FAT1 knockdown seems to impair neuronal migration [27]. ...
... Notably, FAT1 knockdown in epithelial cells impaired migration in a scratchwound assay, and this was associated with deficient lamellipodia formation and the loss of cell polarity [25]. Interestingly, in the process of neural tube closure during mouse development, FAT1 knockdown seems to impair neuronal migration [27]. ...
Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly to the progression of several cardiovascular diseases. VSMC migration specifically supports atherosclerosis, restenosis after catheter-based intervention, transplant vasculopathy, and vascular remodeling during the formation of aneurysms. The atypical cadherin FAT1 is expressed robustly in activated VSMCs and promotes their migration. A positive role of FAT1 in the migration of other cell types, including neurons, fibroblasts, podocytes, and astrocyte progenitors, has also been described. In cancer biology, however, the effect of FAT1 on migration depends on the cancer type or context, as FAT1 either suppresses or enhances cancer cell migration and invasion. With this review, we describe what is known about FAT1’s effects on cell migration as well as the factors that influence FAT1-dependent migration. In VSMCs, these factors include angiotensin II, which activates FAT1 expression and cell migration, and proteins of the Atrophin family: Atrophin-1 and the short isoform of Atrophin-2, which promote VSMC migration, and the long isoform of Atrophin-2, which exerts negative effects on FAT1-dependent VSMC migration.
... For DEE, FAT4, a gene encoding for a protocadherin, a calcium-dependent cell adhesion protein showed the highest developmental score (Fig. 2B). FAT4, which was previously related to epilepsy 40 , plays a role in the maintenance of planar cell polarity as well as in neuroprogenitor proliferation 41 . For GGE, ROR2 is the leading gene in respect to the developmental score. ...
Previous studies suggested that severe epilepsies e.g., developmental and epileptic encephalopathies (DEE) are mainly caused by ultra-rare de novo genetic variants. For milder phenotypes, rare genetic variants could contribute to the phenotype. To determine the importance of rare variants for different epilepsy types, we analyzed a whole-exome sequencing cohort of 9,170 epilepsy-affected individuals and 8,436 controls. Here, we separately analyzed three different groups of epilepsies: severe DEEs, genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We required qualifying rare variants (QRVs) to occur in controls at a minor allele frequency ≤ 1:1,000, to be predicted as deleterious (CADD≥20), and to have an odds ratio in epilepsy cases ≥2. We identified genes enriched with QRVs in DEE (n=21), NAFE (n=72), and GGE (n=32). Enrichment was strongest in NAFE and weakest in DEE. This suggests that rare variants may play a more important role for causality of NAFE than in DEE. Moreover, we found that QRV-carrying genes e.g., HSGP2, FLNA or TNC are involved in structuring the brain extracellular matrix. The present study confirms an involvement of rare variants for NAFE, while in DEE and GGE, the contribution of such variants appears more limited.
... Excessive neuroepithelial proliferation has repeatedly been associated with failure of neural tube closure in mouse genetic models (Lardelli et al., 1996, Parchem et al., 2015, Badouel et al., 2015. ...
Neuroepithelial cells balance tissue growth requirement with the morphogenetic imperative of closing the neural tube. They apically constrict to generate mechanical forces which elevate the neural folds, but are thought to apically dilate during mitosis. However, we previously reported that mitotic neuroepithelial cells in the mouse posterior neuropore have smaller apical surfaces than non-mitotic cells. Here, we document progressive apical enrichment of non-muscle myosin-II in mitotic, but not non-mitotic, neuroepithelial cells with smaller apical areas. Live-imaging of the chick posterior neuropore confirms apical constriction synchronised with mitosis, reaching maximal constriction by anaphase, before division and re-dilation. Mitotic apical constriction amplitude is significantly greater than interphase constrictions. To investigate conservation in humans, we characterised early stages of iPSC differentiation through dual SMAD-inhibition to robustly produce pseudostratified neuroepithelia with apically enriched actomyosin. These cultured neuroepithelial cells achieve an equivalent apical area to those in mouse embryos. iPSC-derived neuroepithelial cells have large apical areas in G2 which constrict in M phase and retain this constriction in G1/S. Given that this differentiation method produces anterior neural identities, we studied the anterior neuroepithelium of the elevating mouse mid-brain neural tube. Instead of constricting, mid-brain mitotic neuroepithelial cells have larger apical areas than interphase cells. Tissue geometry differs between the apically convex early midbrain and flat posterior neuropore. Culturing human neuroepithelia on equivalently convex surfaces prevents mitotic apical constriction. Thus, neuroepithelial cells undergo high-amplitude apical constriction synchronised with cell cycle progression but the timing of their constriction if influenced by tissue geometry.
... Fat1 and Fat4 protocadherins show genetic interaction in cranial neural tube closure, and loss of their functions in mice causes exencephaly [142,143]. They may function as cis-heterodimers to modulate cytoskeletal organization and apical constriction [142]. ...
... Fat1 and Fat4 protocadherins show genetic interaction in cranial neural tube closure, and loss of their functions in mice causes exencephaly [142,143]. They may function as cis-heterodimers to modulate cytoskeletal organization and apical constriction [142]. However, it is unclear whether they regulate polarized cell behaviors and cell-cell interaction by forming ligand-receptor pairs with Dchs protocadherins. ...
Gastrulation and neurulation are successive morphogenetic processes that play key roles in shaping the basic embryonic body plan. Importantly, they operate through common cellular and molecular mechanisms to set up the three spatially organized germ layers and to close the neural tube. During gastrulation and neurulation, convergent extension movements driven by cell intercalation and oriented cell division generate major forces to narrow the germ layers along the mediolateral axis and elongate the embryo in the anteroposterior direction. Apical constriction also makes an important contribution to promote the formation of the blastopore and the bending of the neural plate. Planar cell polarity proteins are major regulators of asymmetric cell behaviors and critically involved in a wide variety of developmental processes, from gastrulation and neurulation to organogenesis. Mutations of planar cell polarity genes can lead to general defects in the morphogenesis of different organs and the co-existence of distinct congenital diseases, such as spina bifida, hearing deficits, kidney diseases, and limb elongation defects. This review outlines our current understanding of non-canonical Wnt signaling, commonly known as Wnt/planar cell polarity signaling, in regulating morphogenetic movements of gastrulation and neural tube closure during development and disease. It also attempts to identify unanswered questions that deserve further investigations.
... We showed that Fat3 is expressed in the proliferating progenitor cells at early developmental stages and also detected in the differentiated neuronal cells including motor neurons in the mantle area at later developmental stages of mouse and chick spinal cords. Fat3 functions to enhance proliferation and inhibit differentiation of neural progenitors, which interestingly is the opposite of the functions known for its other family members Fat1 and Fat4 24,28 . We propose a model in which Fat3 interacts with and suppresses the protein levels and the kinase activity of Lats1/2, thereby stabilizing the downstream effector Yap (Fig. 6B). ...
... It has been shown that Fat1 and Fat4/Fat-J play crucial roles in mouse brain development. Loss of Fat1 and Fat4/Fat-J in mouse embryos results in neural tube closure defects, increased neural progenitor proliferation, and altered apical constrictions, possibly through Fat1 and Fat4 heterodimer formation 28 . Moreover, loss of Fat1 and Fat4 in murine cortices displays enhanced radial precursor proliferation and delayed cell cycle exit 28 . ...
... Loss of Fat1 and Fat4/Fat-J in mouse embryos results in neural tube closure defects, increased neural progenitor proliferation, and altered apical constrictions, possibly through Fat1 and Fat4 heterodimer formation 28 . Moreover, loss of Fat1 and Fat4 in murine cortices displays enhanced radial precursor proliferation and delayed cell cycle exit 28 . In addition, holoprosencephaly and anophthalmia are observed in Fat1 deficient mice 30 . ...
Early embryonic development of the spinal cord requires tight coordination between proliferation of neural progenitors and their differentiation into distinct neuronal cell types to establish intricate neuronal circuits. The Hippo pathway is one of the well-known regulators to control cell proliferation and govern neural progenitor cell number, in which the downstream effector Yes-associated protein (Yap) promotes cell cycle progression. Here we show that an atypical cadherin Fat3, expressed highly in the neural tube, plays a critical role in maintaining proper number of proliferating progenitors. Knockdown of Fat3 in chick neural tube down-regulates expression of the proliferation markers but rather induces the expression of neural markers in the ventricular zone. We further show that deletion of Fat3 gene in mouse neural tube depletes neural progenitors, accompanied by neuronal gene expression in the ventral ventricular zone of the spinal cord. Finally, we found that Fat3 regulates the phosphorylation level of Lats1/2, the upstream kinase of Yap, resulting in dephosphorylation and stabilization of Yap, suggesting Yap as a key downstream effector of Fat3. Our study uncovers another layer of regulatory mechanisms in controlling the activity of Hippo signaling pathway to regulate the size of neural progenitor pools in the developing spinal cord.
... AC is responsible for the generation of forces that lead to epithelial folding, driving the bending of the neuroepithelium in vertebrates (Lee et al., 1983;Sawyer et al., 2010;Inoue et al., 2016). Importantly, ablation of genes regulating AC results in NTDs (Hildebrand and Soriano, 1999;Haigo et al., 2003;Badouel et al., 2015;Grego-Bessa et al., 2015). ...
Neural tube closure (NTC) is a fundamental process during vertebrate development and is indispensable for the formation of the central nervous system. Here, using Xenopus laevis embryos, live imaging, single-cell tracking, optogenetics and loss of function experiments we examine the roles of convergent extension and apical constriction, and define the role of the surface ectoderm during NTC. We show that NTC is a two-stage process with distinct spatiotemporal contributions of convergent extension and apical constriction at each stage. Convergent extension takes place during the first stage and is spatially restricted at the posterior tissue, while apical constriction occurs during the second stage throughout the neural plate. We go on to show that the surface ectoderm is mechanically coupled with the neural plate and its movement during NTC is driven by neural plate morphogenesis. Last, we show that increase of surface ectoderm resistive forces is detrimental for neural plate morphogenesis.
... FAT1-mediated control of cell proliferation is not limited to SMC biology. Global genetic inactivation of Fat1 in mice results in developmental cranial defects in neural tube closure associated with enhanced proliferation of cortical precursors; moreover, in utero knockdown of Fat1 in cortical precursors results in higher proliferation of radial glial precursors (45). Likewise, loss of FAT1 in mice leads to fully penetrant lens epithelial defects during development characterized by increased epithelial cell proliferation (46). ...
Smooth muscle cells contribute to cardiovascular disease, the leading cause of death worldwide. The capacity of these cells to undergo phenotypic switching in mature arteries of the systemic circulation underlies their pathogenic role in atherosclerosis and restenosis, among other vascular diseases. Growth factors and cytokines, extracellular matrix components, regulation of gene expression, neuronal influences, and mechanical forces contribute to smooth muscle cell phenotypic switching. Comparatively little is known about cell metabolism in this process. Studies of cancer and endothelial cell biology have highlighted the importance of cellular metabolic processes for phenotypic transitions that accompany tumor growth and angiogenesis. However, the understanding of cell metabolism during smooth muscle cell phenotypic modulation is incipient. Studies of the atypical cadherin FAT1, which is strongly upregulated in smooth muscle cells in response to arterial injury, suggest that it has important and distinctive functions in this context, mediating control of both smooth muscle cell mitochondrial metabolism and cell proliferation. Here we review the progress made in understanding how FAT1 affects the smooth muscle cell phenotype, highlighting the significance of FAT1 as a processed protein and unexpected regulator of mitochondrial respiration. These mechanisms suggest how a transmembrane protein may relay signals from the extracellular milieu to mitochondria to control metabolic activity during smooth muscle cell phenotypic switching.
... Fat-like's effects on polarity do not depend on Dachsous (Viktorinová et al., 2009), and no ligands for its vertebrate orthologs Fat1 and Fat3 have been described. In vertebrates, Fat1, Fat3, and Fat4 act both synergistically and independently to organize tissue morphogenesis, growth, and cell migration, including in the nervous system (Badouel et al., 2015;Cappello et al., 2013;Deans et al., 2011;Gee et al., 2016;Hou et al., 2006;Krol et al., 2016;Miyazaki, 2011;Moeller et al., 2004;Tanoue and Takeichi, 2004;Zakaria et al., 2014). ...
... For instance, the presence of even one copy of the Fat3-ECD is inhibitory, as evidenced by the Fat3 ΔICD−GFP phenotype in the IPL ( Figure 5). This dominant negative effect, which is also seen in AC migration ( Figure S3), may be caused by cis interactions between WT and mutant proteins, as have been observed to occur among other Fat-related proteins (Badouel et al., 2015). Notably, during synaptogenesis, ACs produce a form of Fat3 with an insertion in its ECD that could alter ligand binding and thus further diversify Fat3's effects on AC development, maturation, and function ( Figure S2). ...
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.
