Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates and humans.
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ABSTRACT:
PROVIDER: PRJNA941252 | ENA |
REPOSITORIES: ENA
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Project description:Spinal motor neurons have been implicated in the loss of motor function that occurs with advancing age. However, the cellular and molecular mechanisms that impair the function of these neurons during aging remain unknown. Here, we show that motor neurons do not die in old female and male mice, rhesus monkeys, and humans. Instead, these neurons selectively shed excitatory synaptic inputs throughout the soma and dendritic arbor during aging. By examining the translatome , we also show that aging alters the molecular composition of motor neurons in both male and female mice. Aging motor neurons present with changes in genes and molecular pathways with roles in glia-mediated synaptic pruning, and inflammation. They also exhibit changes in pathways with roles in axonal regeneration caused by axotomy and Amyotrophic Lateral Sclerosis (ALS). Thus, we have identified cellular and molecular mechanisms altered in aged motor neurons that could serve as therapeutic targets to preserve motor function during aging.
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Project description:Mammalian motor circuits control voluntary movements by transmitting signals from the central nervous system (CNS) to muscle targets. To form these circuits, motor neurons (MNs) must extend their axons out of the CNS. Although motor axon exit from the CNS is an indispensable phase of motor axon pathfinding, the underlying molecular mechanisms remain obscure. Here, we present the first identification of a genetic pathway that regulates motor axon exit from the vertebrate spinal cord, utilizing spinal accessory motor neurons (SACMN) as a model system. SACMN are a homogeneous population of spinal MNs whose axons leave the CNS through a discrete lateral exit point (LEP) and can be visualized by the expression of the cell surface protein, BEN. We show that the homeodomain transcription factor, Nkx2.9, is selectively required for SACMN axon exit and identify the Robo2 guidance receptor as a likely downstream effector of Nkx2.9; loss of Nkx2.9 leads to a reduction in Robo2 mRNA and protein within SACMN and SACMN axons fail to exit the spinal cord in Robo2-deficient mice. Consistent with short-range interactions between Robo2 and Slit ligands regulating SACMN axon exit, Robo2-expressing SACMN axons normally navigate through LEP-associated Slits as they emerge from the spinal cord, and fail to exit in Slit-deficient mice. Our studies support the view that Nkx2.9 controls SACMN axon exit from the mammalian spinal cord by regulating Robo-Slit signaling. We utilized microarray technology to identify novel downstream effectors of the homeodomain transcription factor, Nkx2.9, that regulate spinal accessory motor neuron development.
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Project description:Spinal motor neurons (MNs) integrate sensory stimuli and brain commands to generate movements. In vertebrates, the molecular identities of the cardinal MN types such as those innervating limb versus trunk muscles have been well elucidated. Yet the identities of finer subtypes within these cell populations that innervate individual muscle groups remain enigmatic. Using single-cell transcriptomics, we have investigated heterogeneity in mouse MNs and discovered many unreported MN subtypes. Among limb-innervating MNs, we reveal a surprisingly diverse neuropeptide code for delineating putative motor pool identities. Additionally, we have uncovered that axial MNs are subdivided into three molecularly distinct subtypes, defined by mediolaterally-biased Satb2, Nr2f2 or Bcl11b expression patterns with different axon guidance signatures. These three subtypes are present in chicken and human embryos, suggesting a conserved axial MN expression pattern across higher vertebrates. Overall, our study provides a comprehensive molecular resource of spinal MN types and paves the way towards deciphering how neuronal subtypes evolved to accommodate vertebrate motor behaviors associated with different lifestyles.
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Project description:The spinal cord contains neural networks that enable regionally-distinct motor outputs along the body axis. Nevertheless, it remains unclear how segment-specific motor computations are processed because the cardinal interneuron classes that control motor neurons appear uniform at each level of the spinal cord. V2a interneurons are essential to both fore and hindlimb movements and here we identified two major types that emerge during development: Type-I neurons marked by high Chx10 form recurrent networks with neighboring spinal neurons, and Type-II that downregulate Chx10 and project to supraspinal structures. Type-I and -II V2a interneurons are arrayed in counter-gradients and this network activates different patterns of motor output at cervical and lumbar levels. Single cell RNA-seq revealed Type-I and -II V2a neurons are each comprised of multiple subtypes. Our findings uncover a molecular and anatomical organization of V2a interneurons reminiscent of the orderly way motor neurons are divided into columns and pools.
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Project description:Mammalian motor circuits control voluntary movements by transmitting signals from the central nervous system (CNS) to muscle targets. To form these circuits, motor neurons (MNs) must extend their axons out of the CNS. Although motor axon exit from the CNS is an indispensable phase of motor axon pathfinding, the underlying molecular mechanisms remain obscure. Here, we present the first identification of a genetic pathway that regulates motor axon exit from the vertebrate spinal cord, utilizing spinal accessory motor neurons (SACMN) as a model system. SACMN are a homogeneous population of spinal MNs whose axons leave the CNS through a discrete lateral exit point (LEP) and can be visualized by the expression of the cell surface protein, BEN. We show that the homeodomain transcription factor, Nkx2.9, is selectively required for SACMN axon exit and identify the Robo2 guidance receptor as a likely downstream effector of Nkx2.9; loss of Nkx2.9 leads to a reduction in Robo2 mRNA and protein within SACMN and SACMN axons fail to exit the spinal cord in Robo2-deficient mice. Consistent with short-range interactions between Robo2 and Slit ligands regulating SACMN axon exit, Robo2-expressing SACMN axons normally navigate through LEP-associated Slits as they emerge from the spinal cord, and fail to exit in Slit-deficient mice. Our studies support the view that Nkx2.9 controls SACMN axon exit from the mammalian spinal cord by regulating Robo-Slit signaling.
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