Sox1 Is Required for the Specification of a Novel p2-Derived Interneuron Subtype in the Mouse Ventral Spinal Cord

Abstract

During mouse development, the ventral spinal cord becomes organized into five progenitor domains that express different combinations of transcription factors and generate different subsets of neurons and glia. One of these domains, known as the p2 domain, generates two subtypes of interneurons, V2a and V2b. Here we have used genetic fate mapping and loss-of-function analysis to show that the transcription factor Sox1 is expressed in, and is required for, a third type of p2-derived interneuron, which we named V2c. These are close relatives of V2b interneurons, and, in the absence of Sox1, they switch to the V2b fate. In addition, we show that late-born V2a and V2b interneurons are heterogeneous, and subsets of these cells express the transcription factor Pax6. Our data demonstrate that interneuron diversification in the p2 domain is more complex than previously thought and directly implicate Sox1 in this process.

Commissural axonal corridors instruct neuronal migration in the mouse spinal cord

“…Importantly, this is at least in part due to a cell non-autonomous effect of commissural axons on ipsilateral neuron cell bodies, as Robo3 is exclusively expressed in commissural neurons and V2a neurons are reported to be exclusively ipsilaterally projecting (not Robo3 expressing) neurons, yet are mis-localized in Robo3 À / À embryos 24,31 . Similarly, evidence points to V2c neurons being ipsilaterally projecting neurons, do not express Robo3 and are also are mis-localized in Robo3 À / À embryos 28,31 . Moreover, the finding that perturbation of dorsal commissural neurons by partial ablation of the dorsal spinal cord also results in mispositioning of ventral interneuron cell bodies further supports this model.…”

“…1) 22,27 . We examined the migration of cell bodies from both predominantly commissurally projecting neurons, V0 and V3 neurons, and V2a and V2c neurons, which are likely to be ipsilaterally projecting populations [28][29][30][31][32][33] . The nuclear position of these neuronal subpopulations were identified by transcription factor labelling, V0v/V0cg referred to in text as V0 (Evx1/2 þ ), V2a (Chx10 þ ), V2c (Sox1 þ ) and V3 (Nkx2.2 þ ) neurons 21 .…”

“…To describe this phenomenon, we have coined the term 'axon-restricted migration'. Sox1 þ labels precursors in the ventricular zone and post-mitotic V2c neurons 28 . Sox1 þ V2c migrated first through the medial commissural axon fascicle and then migrated ventrally on the lateral side of it to settle in a position close to the floor plate.…”

Generation of V2a Interneurons from Mouse Embryonic Stem Cells

“…V2a interneurons are excitatory, glutamatergic, and express Chx10 and Lhx3 [17,18,26], whereas V2b interneurons are inhibitory, GABAergic/glycinergic, and express Gata3 [24,[27][28][29][30][31][32]. Newly identified V2c interneurons arise from a subset of V2b interneurons, and their function in CPG networks is still unknown [33,34]. Endogenous Notch-1 signaling has been shown to influence the fate of p2 progenitors, with high Notch-1 signaling favoring differentiation into V2b interneurons over V2a interneurons [25].…”

Asymmetric activation of Dll4-Notch signaling by Foxn4 and proneural factors activates BMP/TGFβ signaling to specify V2b interneurons in the spinal cord

“…To examine the biological relevance of the mosaic expression pattern of the proneural factors, we extended our expression analysis to Foxn4 -/-spinal cords, where more V2a cells are generated at the expense of V2b neurons (Li et al, 2005;Panayi et al, 2010). Notably, at all stages of neurogenesis in wild-type embryos (E10.5-E12.5), there is complete overlap in expression of Ascl1 and Foxn4 in p2 progenitors ( Fig.…”