Origin of a Non-Clarke’s Column Division of the Dorsal Spinocerebellar Tract and the Role of Caudal Proprioceptive Neurons in Motor Function

Abstract

Summary Proprioception, the sense of limb and body position, is essential for generating proper movement. Unconscious proprioceptive information travels through cerebellar-projecting neurons in the spinal cord and medulla. The progenitor domain defined by the basic helix-loop-helix (bHLH) transcription factor, ATOH1, has been implicated in forming these cerebellar-projecting neurons; however, their precise contribution to proprioceptive tracts and motor behavior is unknown. Significantly, we demonstrate that Atoh1-lineage neurons in the spinal cord reside outside Clarke’s column (CC), a main contributor of neurons relaying hindlimb proprioception, despite giving rise to the anatomical and functional correlate of CC in the medulla, the external cuneate nucleus (ECu), which mediates forelimb proprioception. Elimination of caudal Atoh1-lineages results in mice with relatively normal locomotion, but unable to perform coordinated motor tasks. Altogether, we reveal that proprioceptive nuclei in the spinal cord and medulla develop from more than one progenitor source suggesting an avenue to uncover distinct proprioceptive functions.

Making sense out of spinal cord somatosensory development

“…SCTs consist of an ipsilateral-projecting population (the dorsal SCT, DSCT) and a contralateral-projecting population (the ventral SCT, VSCT). Studies have shown that dI1i and dI1c neurons contribute to both the DSCT and VSCT, respectively (Bermingham et al, 2001;Miesegaes et al, 2009;Wilson et al, 2008;Yuengert et al, 2015). However, recent work using Atoh1 lineage tracing shows that the dI1 population only makes a subset of the DSCT and VSCT, suggesting that there are other developmental sources for these tracts (Yuengert et al, 2015).…”

“…5). Indeed, Atoh1 lineage neurons (dI1), which are born from the dorsal-most progenitor domain, migrate ventrally to the intermediate gray area of the spinal cord (laminae V-VII) with a smattering of neurons even reaching the ventral horn (Miesegaes et al, 2009;Wilson et al, 2008;Yuengert et al, 2015). In addition, dI2 and dI3 neurons settle in the intermediate to ventral parts of the spinal cord (Bui et al, 2013;Hadas et al, 2014;Quinones et al, 2010).…”

“…However, neurons that have been defined by anatomical characteristics may arise from more than one developmental population. For example, dorsal spinocerebellar tract (DSCT) neurons derive from at least two developmental sources: dI1i and as yet unknown sources (Yuengert et al, 2015). Similarly, Ia inhibitory interneurons in the ventral spinal cord derive from both V1 and V2b (Zhang et al, 2014), and propriospinal neurons that target motor neurons and the lateral reticular nucleus have been shown to derive from several developmental populations (dI3, V1, V2, V3) (Pivetta et al, 2014).…”

“…This sense is detected by sensory neurons (see Box 2) such as group Ia, Ib, and II fibers that detect changes in muscle length and tension. Spinal targets of these sensory neurons, largely labeled by parvalbumin (PV) (Arber et al, 2000;de Nooij et al, 2013), include secondary neurons in spinal cord that send this information up to the cerebellum (via spinocerebellar tracts, SCTs) (Brown, 1981;Oscarsson, 1965;Yuengert et al, 2015) and motor neurons for monosynaptic reflex arcs (Arber et al, 2000). SCTs consist of an ipsilateral-projecting population (the dorsal SCT, DSCT) and a contralateral-projecting population (the ventral SCT, VSCT).…”

“…These defined populations can be further divided into subtypes using criteria such as axonal projections, resulting location in the spinal cord and neuropeptide expression. For example, the dI1 population can be split into two populations that are distinguished by their spatial location and axonal projections: dI1i (ipsilaterally projecting) and dI1c (contralaterally projecting) (Miesegaes et al, 2009;Wilson et al, 2008;Yuengert et al, 2015). These 13 main population designations are central to understanding how TF expression is patterned in response to morphogens and how TFs specify neuronal identity.…”