Renshaw cell interneuron specialization is controlled by a temporally restricted transcription factor program

Abstract

SUMMARYThe spinal cord contains a diverse array of physiologically distinct interneuron cell types that subserve specialized roles in somatosensory perception and motor control. The mechanisms that generate these specialized interneuronal cell types from multipotential spinal progenitors are not known. In this study, we describe a temporally regulated transcriptional program that controls the differentiation of Renshaw cells (RCs), an anatomically and functionally discrete spinal interneuron subtype. We show that the selective activation of the Onecut transcription factors Oc1 and Oc2 during the first wave of V1 interneuron neurogenesis is a key step in the RC differentiation program. The development of RCs is additionally dependent on the forkhead transcription factor Foxd3, which is more broadly expressed in postmitotic V1 interneurons. Our demonstration that RCs are born, and activate Oc1 and Oc2 expression, in a narrow temporal window leads us to posit that neuronal diversity in the developing spinal cord is established by the composite actions of early spatial and temporal determinants.

The late and dual origin of cerebrospinal fluid-contacting neurons in the mouse spinal cord

“…Although other cases have been reported in which the temporal component contributes to neuronal diversity in the spinal cord (Gross et al, 2002;Stam et al, 2012), we provide robust evidence of neuronal differentiation occurring in what has been classically termed the gliogenic phase, proving that neurogenic potential is retained in the late ventricular zone progenitors.…”

“…Evidence of temporal developmental programs within restricted progenitor territories in the spinal cord includes dorsal Lbx1 + interneurons that are produced in consecutive neurogenic waves (Gross et al, 2002), and Renshaw cells, which constitute the earliest-born subset of V1 neurons (Stam et al, 2012;Sapir et al, 2004).…”

Making sense out of spinal cord somatosensory development

“…Therefore, function can partially be separated by birth date, but again the neurons reside scattered across lamina V-VII following no particular laminar distribution (Tripodi et al, 2011). Similarly, birth date can distinguish the formation of Renshaw cells and Ia inhibitory interneurons that derive from the V1 progenitor domain in the ventral spinal cord (Benito-Gonzalez and Alvarez, 2012;Stam et al, 2012). Altogether, although the organization of the progenitors does not prefigure the organization of the spinal cord with regards to lamina distribution, they do predict where particular developmental lineages settle in the adult spinal cord and dictate some functional properties of these neurons.…”

Onecut transcription factors act upstream of Isl1 to regulate spinal motoneuron diversification

“…These proteins are detected during development in several endodermal derivatives including liver and pancreas, where they redundantly control different aspects of cell fate decision and morphogenetic processes (Jacquemin et al, 2000;Clotman et al, 2002;Jacquemin et al, 2003a;Pierreux et al, 2006;Vanhorenbeeck et al, 2007). They are also present in the embryonic CNS (Landry et al, 1997;Jacquemin et al, 2003b;Vanhorenbeeck et al, 2007), where they regulate the generation, maintenance or the projections of different encephalic structures (Hodge et al, 2007;Chakrabarty et al, 2012;Espana and Clotman, 2012a;Espana and Clotman, 2012b) and of a spinal interneuron population (Stam et al, 2012). In the ventral spinal cord, the three OC genes are differentially and dynamically expressed during the early steps of MN differentiation (Francius and Clotman, 2010), suggesting that OC factors might contribute to spinal MN development.…”