Hox Repertoires for Motor Neuron Diversity and Connectivity Gated by a Single Accessory Factor, FoxP1

Smilow Neuroscience Program, Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA.
Cell (Impact Factor: 32.24). 08/2008; 134(2):304-16. DOI: 10.1016/j.cell.2008.06.019
Source: PubMed


The precision with which motor neurons innervate target muscles depends on a regulatory network of Hox transcription factors that translates neuronal identity into patterns of connectivity. We show that a single transcription factor, FoxP1, coordinates motor neuron subtype identity and connectivity through its activity as a Hox accessory factor. FoxP1 is expressed in Hox-sensitive motor columns and acts as a dose-dependent determinant of columnar fate. Inactivation of Foxp1 abolishes the output of the motor neuron Hox network, reverting the spinal motor system to an ancestral state. The loss of FoxP1 also changes the pattern of motor neuron connectivity, and in the limb motor axons appear to select their trajectories and muscle targets at random. Our findings show that FoxP1 is a crucial determinant of motor neuron diversification and connectivity, and clarify how this Hox regulatory network controls the formation of a topographic neural map.

Download full-text


Available from: Jeremy S Dasen, Jan 13, 2014
  • Source
    • "To determine the rostro-caudal spinal cord identity of these motor neuron subtypes, we analyzed the expression of specific HOX genes by QPCR. We found that HOXC8, HOXC9 and HOXC10, markers for brachial, thoracic and lumbar motor neurons, respectively (Dasen et al., 2008), are strongly expressed in purified motor neurons (Fig. 4C). Taken together, these data indicate that the purified motor neurons contain a Fig. 2. FACS-isolation of human iPSc-derived motor neurons. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease. Human motor neurons generated from induced pluripotent stem cells (iPSc) offer new perspectives for disease modeling and drug testing in ALS. In standard iPSc-derived cultures however, the two major phenotypic alterations of ALS - degeneration of motor neuron cell bodies and axons - are often obscured by cell body clustering, extensive axon criss-crossing and presence of unwanted cell types. Here, we succeeded to isolate 100% pure and standardized human motor neurons by a novel FACS double selection based on a p75(NTR) surface epitope and an HB9:RFP lentivirus reporter. The p75(NTR)/HB9::RFP motor neurons survive and grow well without forming clusters or entangled axons, are electrically excitable, contain ALS-relevant motor neuron subtypes and form functional connections with co-cultured myotubes. Importantly, they undergo rapid and massive cell death and axon degeneration in response to mutant SOD1 astrocytes. These data demonstrate the potential of FACS-isolated human iPSc-derived motor neurons for improved disease modeling and drug testing in ALS and related motor neuron diseases. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Neurobiology of Disease
  • Source
    • "PGC MNs are FOXP1 + /ISL1 + /HB9 À , while HMC MNs are LHX3 À /FOXP1 À but express both HB9 and ISL1 (Dasen et al., 2008; William et al., 2003). Thus, quantitative immunocytochemistry can be used to observe whether cervical, thoracic, and lumbar neuroectoderm could be differentiated into MN precursors populations exhibiting relative FOXP1/HB9 co-expression patterns characteristic of their R/C domain in vivo, i.e., the presence of FOXP1 + / HB9 + cells in cervical and lumbar but not thoracic cultures (Dasen et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Colinear HOX expression during hindbrain and spinal cord development diversifies and assigns regional neural phenotypes to discrete rhombomeric and vertebral domains. Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions. Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/β-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2(+)/Brachyury(+) neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days. Switching to retinoic acid treatment at any point during this process halts colinear HOX activation and transitions the neuromesoderm into SOX2(+)/PAX6(+) neuroectoderm with predictable, discrete HOX gene/protein profiles that can be further differentiated into region-specific cells, e.g., motor neurons. This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Stem Cell Reports
  • Source
    • "Their results demonstrate that within a specific rostro-caudal segment, cross-repressive interactions between HOX members produce a unique combinatorial code that directs MN pool identity (Dasen et al., 2005; Lacombe et al., 2013). This identity is revealed by the activation of pool specific proteins such as the ETV1 and ETV4 (or PEA3) (Lin et al., 1998; Ladle and Frank, 2002; Livet et al., 2002), RUNX1 (Theriault et al., 2004; Dasen et al., 2005; Stifani et al., 2008; Zagami et al., 2009; Lamballe et al., 2011) and POU3F1 (Dasen et al., 2005; Rousso et al., 2008). By doing so, Dasen et al. (2005) have remarkably linked the intrinsic HOX combinatorial network to extrinsically induced factors whose expressions are dependent on a signal from the periphery (Lin et al., 1998; Haase et al., 2002) described in more detail below. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Oct 2014 · Frontiers in Cellular Neuroscience
Show more