Spinal motor neurons are specified to innervate different muscle targets through combinatorial programs of transcription factor expression. Whether transcriptional programs also establish finer aspects of motor neuron subtype identity, notably the prominent functional distinction between alpha and gamma motor neurons, remains unclear. In this study, we identify DNA binding proteins with complementary expression profiles in alpha and gamma motor neurons, providing evidence for molecular distinctions in these two motor neuron subtypes. The transcription factor Err3 is expressed at high levels in gamma but not alpha motor neurons, whereas the neuronal DNA binding protein NeuN marks alpha but not gamma motor neurons. Signals from muscle spindles are needed to support the differentiation of Err3 on /NeuN off presumptive gamma motor neurons, whereas direct proprioceptive sensory input to a motor neuron pool is apparently dispensable. Together, these findings provide evidence that transcriptional programs define functionally distinct motor neuron subpopulations, even within anatomically defined motor pools.motor neuron ͉ spinal cord ͉ transcription factors N euronal diversity underlies many features of central nervous system (CNS) organization and function. Neurons located within different regions of the CNS typically exhibit distinct morphologies and patterns of connectivity that help to determine their physiological functions. Within a single region, neurons that serve closely related functions can be further subdivided, both anatomically and physiologically. The retina, for example, contains multiple subclasses of ganglion and amacrine neurons that are distinguishable by position, patterns of dendritic arborization, and their role in visual processing (1, 2). Similarly, the cerebral cortex contains many local circuit interneurons, each with specialized anatomy, circuitry, and physiology (3). Little is known, however, about how such fine distinctions in CNS neuronal subtype identity and connectivity are assigned.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 determinants, acting in a hierarchical manner to assign subtype identities to a generic set of motor neurons (4, 5). The motor neurons that project to skeletal muscle targets can be subdivided into distinct columnar subgroups, each projecting to a different target domain-axial, body wall, and limb targets. The lateral motor column (LMC) neurons that project their axons to limb muscles can be further subdivided into divisional and pool subclasses that, together, specify the pattern of target muscle connectivity (4, 5). The sequential steps involved in controlling motor neuron subtype identities and target projections are programmed through the cell-type selectivity of transcription factor expression, notably members of the Hox, LIM, Nkx6, and ETS families (6-10). Thus combinatorial programs of transcription factor expression appear to provide...

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Motor pools comprise a heterogeneous population of motor neurons that innervate distinct intramuscular targets. While the organization of motor neurons into motor pools has been well described, the time course and mechanism of motor pool diversification into functionally distinct classes remains unclear. γ-Motor neurons (γ-MNs) and α-motor neurons (α-MNs) differ in size, molecular identity, synaptic input and peripheral target. While α-MNs innervate extrafusal skeletal muscle fibers to mediate muscle contraction, γ-MNs innervate intrafusal fibers of the muscle spindle, and regulate sensitivity of the muscle spindle in response to stretch. In this study, we find that the secreted signaling molecule Wnt7a is selectively expressed in γ-MNs in the mouse spinal cord by embryonic day 17.5 and continues to molecularly distinguish γ;-from α-MNs into the third postnatal week. Our data demonstrate that Wnt7a is the earliest known γ-MN marker, supporting a model of developmental divergence between α- and γ-MNs at embryonic stages. Furthermore, using Wnt7a expression as an early marker of γ-MN identity, we demonstrate a previously unknown dependence of γ-MNs on a muscle spindle-derived, GDNF-independent signal during the first postnatal week.

Cell-type specific intrinsic programs instruct neuronal subpopulations before target-derived factors influence later neuronal maturation. Retrograde neurotrophin signaling controls neuronal survival and maturation of dorsal root ganglion (DRG) sensory neurons, but how these potent signaling pathways intersect with transcriptional programs established at earlier developmental stages remains poorly understood. Here we determine the consequences of genetic alternation of NT3 signaling on genome-wide transcription programs in proprioceptors, an important sensory neuron subpopulation involved in motor reflex behavior. We find that the expression of many proprioceptor-enriched genes is dramatically altered by genetic NT3 elimination, independent of survival-related activities. Combinatorial analysis of gene expression profiles with proprioceptors isolated from mice expressing surplus muscular NT3 identifies an anticorrelated gene set with transcriptional levels scaled in opposite directions. Voluntary running experiments in adult mice further demonstrate the maintenance of transcriptional adjustability of genes expressed by DRG neurons, pointing to life-long gene expression plasticity in sensory neurons.