Molecular Logic of Spinocerebellar Tract Neuron Diversity and Connectivity

Abstract

Coordinated motor behaviors depend on feedback communication between peripheral sensory systems and central circuits in the brain and spinal cord. Relay of muscle and tendonderived sensory information to the CNS is facilitated by functionally and anatomically diverse groups of spinocerebellar tract neurons (SCTNs), but the molecular logic by which SCTN diversity and connectivity is achieved is poorly understood. We used single cell RNA sequencing and genetic manipulations to define the mechanisms governing the molecular profile and organization of SCTN subtypes. We found that SCTNs relaying proprioceptive sensory information from limb and axial muscles are generated through segmentally-restricted actions of specific Hox genes. Loss of Hox function disrupts SCTN subtype-specific transcriptional programs, leading to defects in the connections between proprioceptive sensory neurons, SCTNs, and the cerebellum. These results indicate that Hox-dependent genetic programs play essential roles in the assembly of the neural circuits required for proprioception.

Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis

“…To determine any underlying structure in our proprioceptor population we employed an iterative clustering method to identify putative groupings of cells with similar transcriptional profile using an algorithm based on Tasic et al 2018, and Baek et al 2019 (see methods). These analyses resulted in the identification of five major clusters (Figure 2B, Figure S4F).…”