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Gamma and Alpha Motor Neurons Distinguished by Expression of Transcription Factor Err3

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Gamma and Alpha Motor Neurons Distinguished by Expression of Transcription Factor Err3 Gamma and alpha motor neurons distinguished by expression of transcription factor Err3 Andreas Friesea, Julia A. Kaltschmidtb,1,2, David R. Ladlea,1,3, Markus Sigrista, Thomas M. Jessellb,4, and Silvia Arbera,5 aBiozentrum, Department of Cell Biology, University of Basel and Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland; and bHoward Hughes Medical Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027 Contributed by Thomas M. Jessell, June 26, 2009 (sent for review June 4, 2009) Spinal motor neurons are specified to innervate different muscle Yet neurons within a single motor pool also exhibit further targets through combinatorial programs of transcription factor subtype distinctions. Most motor pools are composed of a expression. Whether transcriptional programs also establish finer mixture of fast and slow motor neurons (11)—two classes that aspects of motor neuron subtype identity, notably the prominent exhibit distinct profiles of activation, produce different degrees functional distinction between alpha and gamma motor neurons, of force during the process of muscle contraction (11), and show remains unclear. In this study, we identify DNA binding proteins distinct vulnerabilities in motor neuron disease (12). Arguably with complementary expression profiles in alpha and gamma the most prominent distinction between neurons within a motor motor neurons, providing evidence for molecular distinctions in pool, however, is the presence of alpha and gamma motor these two motor neuron subtypes. The transcription factor Err3 is neurons. Alpha and gamma motor neurons differ in morphology, expressed at high levels in gamma but not alpha motor neurons, as well as in their peripheral and central patterns of connectivity whereas the neuronal DNA binding protein NeuN marks alpha but (11). Alpha motor neurons predominate within motor pools and not gamma motor neurons. Signals from muscle spindles are innervate force-generating extrafusal muscle fibers at neuromus- needed to support the differentiation of Err3on/NeuNoff presump- cular junctions (13). Gamma motor neurons constitute approx- tive gamma motor neurons, whereas direct proprioceptive sensory imately one third of all motor neurons within a pool and input to a motor neuron pool is apparently dispensable. Together, innervate the intrafusal muscle fibers found in muscle spindles, these findings provide evidence that transcriptional programs where they modulate the sensitivity of muscle spindles to stretch define functionally distinct motor neuron subpopulations, even (13–16). Gamma and alpha motor neurons also differ profoundly within anatomically defined motor pools. with respect to their soma size and connectivity profile within the spinal cord. Alpha motor neurons have large cell bodies, and motor neuron ͉ spinal cord ͉ transcription factors most receive direct group Ia–derived proprioceptive sensory input (17), whereas gamma motor neurons have small cell bodies euronal diversity underlies many features of central nervous (13) and lack direct input from proprioceptive sensory afferents Nsystem (CNS) organization and function. Neurons located (18). Because almost every motor neuron pool includes gamma within different regions of the CNS typically exhibit distinct and alpha motor neurons, subtype diversification at this in- morphologies and patterns of connectivity that help to deter- trapool level is conceptually different from the broad target– mine their physiological functions. Within a single region, neu- based distinctions that correlate with motor neuron pools. rons that serve closely related functions can be further subdi- The fundamental distinctions in alpha and gamma motor vided, both anatomically and physiologically. The retina, for neuron connectivity and function pose the question of how this finer, intrapool, aspect of motor neuron specification is pro- example, contains multiple subclasses of ganglion and amacrine grammed. Can the principle of transcriptional specification of neurons that are distinguishable by position, patterns of den- motor neuron subtype be extended to the distinction between dritic arborization, and their role in visual processing (1, 2). gamma and alpha motor neurons, features that are independent Similarly, the cerebral cortex contains many local circuit inter- of the identity of the target muscle group? If so, do gamma and neurons, each with specialized anatomy, circuitry, and physiol- alpha motor neurons each possess defining molecular markers, ogy (3). Little is known, however, about how such fine distinc- or do gamma motor neurons simply lack certain of the genes that tions in CNS neuronal subtype identity and connectivity are define alpha motor neuron identity, and vice versa? How do assigned. gamma and alpha motor neurons acquire their diverse anatom- The spinal cord represents a region of the CNS where the diversity of neuronal subtypes has been shown to emerge as a consequence of the expression of intrinsic molecular determi- Author contributions: A.F., J.A.K., D.R.L., M.S., T.M.J., and S.A. designed research; A.F., nants, acting in a hierarchical manner to assign subtype identities J.A.K., D.R.L., M.S., and S.A. performed research; A.F., J.A.K., D.R.L., M.S., T.M.J., and S.A. to a generic set of motor neurons (4, 5). The motor neurons that analyzed data; and J.A.K., T.M.J., and S.A. wrote the paper. project to skeletal muscle targets can be subdivided into distinct The authors declare no conflict of interest. columnar subgroups, each projecting to a different target do- Freely available online through the PNAS open access option. main—axial, body wall, and limb targets. The lateral motor 1J.A.K. and D.R.L. contributed equally to this study. column (LMC) neurons that project their axons to limb muscles 2Present address: Developmental Biology Program, Sloan–Kettering Institute, New York, can be further subdivided into divisional and pool subclasses NY 10065. that, together, specify the pattern of target muscle connectivity 3Present address: Department of Neuroscience, Cell Biology, and Physiology, Wright State (4, 5). The sequential steps involved in controlling motor neuron University, Dayton, OH 45435. subtype identities and target projections are programmed 4To whom correspondence may be addressed at: Columbia University, Howard Hughes through the cell-type selectivity of transcription factor expres- Medical Institute, Departments of Neuroscience and Biochemistry and Molecular Biophys- ics, 701 W 168th Street, New York, NY 10032. E-mail: [email protected]. sion, notably members of the Hox, LIM, Nkx6, and ETS families 5To whom may should be addressed at: Biozentrum, Department of Cell Biology, University (6–10). Thus combinatorial programs of transcription factor of Basel, Klingelbergstrasse 70, 4065 Basel and Friedrich Miescher Institute for Biomedical expression appear to provide the fundamental logic of spinal Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. E-mail: [email protected]. motor neuron diversification and connectivity to specific periph- This article contains supporting information online at www.pnas.org/cgi/content/full/ eral muscle targets. 0906809106/DCSupplemental. 13588–13593 ͉ PNAS ͉ August 11, 2009 ͉ vol. 106 ͉ no. 32 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0906809106 Downloaded by guest on September 26, 2021 ical and functional properties—through cell-intrinsic programs, A putative gamma MNs putative alpha MNs through the influence of peripheral signals, or by virtue of their population 1 population 2 central connectivity? Intriguingly, the muscle fiber targets of m=232.4, sd=50.2 m=776.6, sd=179.7 gamma and alpha motor neurons can be distinguished by tran- scription factor expression; the zinc-finger transcription factor 40 Egr3 and the ETS transcription factors Pea3 and Er81 are 30 sllec# expressed selectively by intrafusal muscle fibers (19–21). Defin- ing molecular markers that distinguish gamma and alpha motor 02010 neurons would provide a first step in addressing the develop- mental specification of intrapool motor neuron subtypes. In this study, we set out to determine whether gamma and 200 400 600 800 1000 1200 1400 alpha motor neurons in the spinal cord of the mouse are MN size: µm2 distinguishable on the basis of their profile of expression of transcription factors and other molecular markers. We uncov- NM/snotuob1Gv# ered two genes with complementary expression profiles in B 30 gamma and alpha motor neurons. Gamma motor neurons ex- 02010 press high levels of the orphan nuclear hormone receptor Err3 (22, 23) and lack expression of neuronal DNA binding protein NeuN (24). Conversely, alpha motor neurons are characterized by low or negligible levels of Err3 and high-level NeuN expres- 200 400 600 800 1000 1200 1400 sion. Mice deficient in muscle spindle differentiation exhibit a MN size: µm2 selective absence of Err3on/NeuNoff presumptive gamma motor neurons. These findings establish that gamma and alpha motor putative gamma MN putative alpha MN neurons are molecularly distinct, and extend the principle that spinal motor neuron subtype identity has its origins in hierar- C D chical programs of transcription factor expression, even within a 1tul single anatomically coherent motor pool. Gv NEUROSCIENCE Results TAh Anatomical Identification of Presumptive Gamma and Alpha Motor C Neurons. Within the mammalian spinal cord, gamma and alpha motor neurons can be distinguished by two main anatomical features.
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