Foxp-Mediated Suppression of N-Cadherin Regulates Neuroepithelial Character and Progenitor Maintenance in the CNS

Department of Neurobiology, David Geffen School of Medicine at UCLA, 610 Charles Young Drive East, Los Angeles, CA 90095, USA.
Neuron (Impact Factor: 15.05). 04/2012; 74(2):314-30. DOI: 10.1016/j.neuron.2012.02.024
Source: PubMed


Neuroepithelial attachments at adherens junctions are essential for the self-renewal of neural stem and progenitor cells and the polarized organization of the developing central nervous system. The balance between stem cell maintenance and differentiation depends on the precise assembly and disassembly of these adhesive contacts, but the gene regulatory mechanisms orchestrating this process are not known. Here, we demonstrate that two Forkhead transcription factors, Foxp2 and Foxp4, are progressively expressed upon neural differentiation in the spinal cord. Elevated expression of either Foxp represses the expression of a key component of adherens junctions, N-cadherin, and promotes the detachment of differentiating neurons from the neuroepithelium. Conversely, inactivation of Foxp2 and Foxp4 function in both chick and mouse results in a spectrum of neural tube defects associated with neuroepithelial disorganization and enhanced progenitor maintenance. Together, these data reveal a Foxp-based transcriptional mechanism that regulates the integrity and cytoarchitecture of neuroepithelial progenitors.

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    • "Sey/Sey mutant mice were generated as previously described (Novitch et al., 2001; Rousso et al., 2012). All mice were maintained and tissue collected in accordance with guidelines set forth by the UCLA Institutional Animal Care and Use Committee. "
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    ABSTRACT: Throughout the developing nervous system, neural stem and progenitor cells give rise to diverse classes of neurons and glia in a spatially and temporally coordinated manner. In the ventral spinal cord, much of this diversity emerges through the morphogen actions of Sonic hedgehog (Shh). Interpretation of the Shh gradient depends on both the amount of ligand and duration of exposure, but the mechanisms permitting prolonged responses to Shh are not well understood. We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates. Notch activity regulates subcellular localization of the Shh receptor Patched1, gating the translocation of the key effector Smoothened to primary cilia and its downstream signaling activities. These data reveal an unexpected role for Notch shaping the interpretation of the Shh morphogen gradient and influencing cell fate determination. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 04/2015; 148(4). DOI:10.1016/j.devcel.2015.03.005 · 9.71 Impact Factor
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    • "What are the molecular mechanisms controlling such migration? Rousso et al. (2012) remarkably identify the role of the forkhead box P2 and 4 (FOXP2/4) in promoting the detachment of newly born MNs from the ventricular zone. Additionally, the authors elegantly linked nuclear gene regulation to effector protein at the membrane. "
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    ABSTRACT: Motor neurons (MNs) are neuronal cells located in the central nervous system (CNS) controlling a variety of downstream targets. This function infers the existence of MN subtypes matching the identity of the targets they innervate. To illustrate the mechanism involved in the generation of cellular diversity and the acquisition of specific identity, this review will focus on spinal MNs (SpMNs) that have been the core of significant work and discoveries during the last decades. SpMNs are responsible for the contraction of effector muscles in the periphery. Humans possess more than 500 different skeletal muscles capable to work in a precise time and space coordination to generate complex movements such as walking or grasping. To ensure such refined coordination, SpMNs must retain the identity of the muscle they innervate. Within the last two decades, scientists around the world have produced considerable efforts to elucidate several critical steps of SpMNs differentiation. During development, SpMNs emerge from dividing progenitor cells located in the medial portion of the ventral neural tube. MN identities are established by patterning cues working in cooperation with intrinsic sets of transcription factors. As the embryo develop, MNs further differentiate in a stepwise manner to form compact anatomical groups termed pools connecting to a unique muscle target. MN pools are not homogeneous and comprise subtypes according to the muscle fibers they innervate. This article aims to provide a global view of MN classification as well as an up-to-date review of the molecular mechanisms involved in the generation of SpMN diversity. Remaining conundrums will be discussed since a complete understanding of those mechanisms constitutes the foundation required for the elaboration of prospective MN regeneration therapies.
    Frontiers in Cellular Neuroscience 10/2014; 8:293. DOI:10.3389/fncel.2014.00293 · 4.29 Impact Factor
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    • "Affected individuals all carry heterozygous mutations in FOXP2, meaning that they still have one functional copy of the gene. A complete loss of FOXP2 is thought to be lethal for humans, as it is in mouse models, likely due to developmental defects in multiple organs (Lu et al., 2002; Shu et al., 2007; Rousso et al., 2012). Although developmentally expressed in many tissues including the brain, lung, and heart, reduced levels of functional FOXP2 results in a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits in patients (Vargha-Khadem et al., 1995; Alcock et al., 2000; Watkins et al., 2002a). "
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    ABSTRACT: FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells.
    Frontiers in Cellular Neuroscience 09/2014; 8:305. DOI:10.3389/fncel.2014.00305 · 4.29 Impact Factor
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