Inhibitor of -catenin and T cell factor (ICAT) inhibits Wnt signaling by interfering with the interaction between -catenin and T cell factor. Here we show that ICAT ؊/؊ embryos exhibit malformation of the forebrain and craniofacial bones and lack the kidney. Analysis of the neuronal differentiation of embryonic stem cells revealed that Wnt3a redirects the fate of neural progenitors to a posterior character, whereas ICAT induces forebrain cells by inhibiting Wnt signaling. Furthermore, ICAT ؊/؊ embryonic stem cells were found to differentiate into neuronal cells possessing a posterior character. These results suggest that ICAT plays an important role in the anteriorization of neural cells by inhibiting the posteriorizing activity of Wnt signaling.W nt signaling plays a crucial role in a number of developmental processes, including body axis formation, development of the central nervous system, and axial specification in limb development (1-8). Wnt signaling stabilizes -catenin, which in turn associates with T cell factor (TCF)͞lymphoid-enhancing factor family transcription factors, ultimately altering the expression of Wnt target genes. In the absence of Wnt signaling, -catenin is recruited into the multiprotein complex containing adenomatous polyposis coli (APC), glycogen synthase kinase-3, casein kinase 1␣, and Axin or the closely related factor conductin͞Axil and subjected to proteasome-mediated degradation. Wnt signaling is further inhibited by the association of -catenin with the inhibitor of -catenin and TCF (ICAT) (9-12). ICAT is an 81-aa protein that interferes with the interaction between -catenin and TCF. ICAT contains an amino-terminal helical domain that binds to armadillo repeats 10-12 of -catenin, and a carboxy-terminal tail that competes with TCF for binding to armadillo repeats 5-10 (9, 11, 12). Overexpression of ICAT induces G 2 arrest and cell death of colorectal tumor cells mutated in APC or -catenin and hepatocellular carcinoma cells mutated in Axin (10).It has been shown that Wnt signaling specifies posterior-toanterior fates within the neural plate (13-16). Inhibition of Wnt signaling is required for anterior specification; negative regulators of Wnt signaling play a crucial role in establishing a gradient of Wnt activity patterning the anterior-posterior axis. Mouse embryos lacking Dickkopf1, a secreted protein that acts as an inhibitor of the Wnt coreceptor low density lipoprotein receptor-related protein 6, lack head structures anterior to the midbrain (17). Also, mouse embryos lacking Six3 (sine oculis homeobox homolog 3), a direct negative regulator of Wnt1 expression, lack forebrain structures and exhibit posteriorization of the remaining mutant heads (18). In addition, zebrafish mutants for the negative intracellular regulators of Wnt signaling tcf3͞headless and axin͞masterblind display anterior defects (19 -21). In the present study, we show that mouse embryos lacking ICAT exhibit multiple defects including malformation of the forebrain. Furthermore, by analyzing the neuron...
The Rho family of small GTPases, including RhoA, Rac1 and Cdc42, are critical regulators of the actin cytoskeleton. In neuronal systems, Rho GTPase-activating proteins (RhoGAPs) and their substrates, Rho GTPases, have been implicated in regulating multiple processes in the morphological development of neurons, including axonal growth and guidance, dendritic elaboration and formation of synapses. RICS is mainly expressed in the brain and functions as a RhoGAP protein for Cdc42 and Rac1 in vitro . To examine the biological function of RICS, we disrupted the RICS gene in mice. RICS knockout mice developed normally and were fertile. However, when cultured in vitro , Cdc42 activity in RICS -/-neurons was higher than that in wild-type neurons. Consistent with this finding, hippocampal and cerebellar granule neurons derived from RICS -/-mice bore longer neurites than those from wild-type mice. These findings suggest that RICS plays an important role in neurite extension by regulating Cdc42 in vivo .
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