Formation of a Protocadherin-19–N-cadherin complex facilitates adhesion by Protocadherin-19 while suppressing homophilic interactions by N-cadherin.

No abstract

Proprioception, the sense of limb and body position, generates a map of the body that is essential for proper motor control, yet we know little about precisely how neurons in proprioceptive pathways develop and are wired. Proprioceptive and cutaneous information from the periphery is sent to secondary neurons in the spinal cord that integrate and relay this information to the cerebellum either directly or indirectly through the medulla. Defining the anatomy of these direct and indirect pathways is fundamental to understanding how proprioceptive circuits function. Here, we use genetic tools in mice to define the developmental origins and unique anatomical trajectories of these pathways. Developmentally, we find that Clarke's column (CC) neurons, a major contributor to the direct spinocerebellar pathway, derive from the Neurog1 progenitor domain. By contrast, we find that two of the indirect pathways, the spino-lateral reticular nucleus (spino-LRt) and spino-olivary pathways, are derived from the Atoh1 progenitor domain, despite previous evidence that Atoh1-lineage neurons form the direct pathway. Anatomically, we also find that the mossy fiber terminals of CC neurons diversify extensively with some axons terminating bilaterally in the cerebellar cortex. Intriguingly, we find that CC axons do not send axon collaterals to the medulla or cerebellar nuclei like other mossy fiber sources. Altogether, we conclude that the direct and indirect spinocerebellar pathways derive from distinct progenitor domains in the developing spinal cord and that the proprioceptive information from CC neurons is processed only at the level of granule cells in the cerebellum.

Proprioception, the sense of limb and body position, generates a map of the body that is essential for proper motor control, yet we know little about precisely how neurons in proprioceptive pathways are wired. Defining the anatomy of secondary neurons in the spinal cord that integrate and relay proprioceptive and potentially cutaneous information from the periphery to the cerebellum is fundamental to understanding how proprioceptive circuits function. Here, we define the unique anatomic trajectories of long-range direct and indirect spinocerebellar pathways as well as local intersegmental spinal circuits using genetic tools in both male and female mice. We find that Clarke's column neurons, a major contributor to the direct spinocerebellar pathway, has mossy fiber terminals that diversify extensively in the cerebellar cortex with axons terminating bilaterally, but with no significant axon collaterals within the spinal cord, medulla, or cerebellar nuclei. By contrast, we find that two of the indirect pathways, the spino-lateral reticular nucleus and spino-olivary pathways, are in part, derived from cervical Atoh1-lineage neurons, whereas thoracolumbar Atoh1-lineage neurons project mostly locally within the spinal cord. Notably, while cervical and thoracolumbar Atoh1-lineage neurons connect locally with motor neurons, no Clarke's column to motor neuron connections were detected. Together, we define anatomic differences between long-range direct, indirect, and local proprioceptive subcircuits that likely mediate different components of proprioceptive-motor behaviors.