Article

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: 33.12). 08/2008; 134(2):304-16. DOI: 10.1016/j.cell.2008.06.019
Source: PubMed

ABSTRACT 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.

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Available from: Jeremy S Dasen, Jan 13, 2014
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    • "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. "
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    • "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). "
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    • "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. "
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