Onecut factors and Pou2f2 regulate the distribution of V2 interneurons in the mouse developing spinal cord

Abstract

32 Acquisition of proper neuronal identity and position is critical for the formation of neural 33 circuits. In the embryonic spinal cord, cardinal populations of interneurons diversify into 34 specialized subsets and migrate to defined locations within the spinal parenchyma. 35 However, the factors that control interneuron diversification and migration remain poorly 36 characterized. Here, we show that the Onecut transcription factors are necessary for proper 37 diversification and distribution of the V2 interneurons in the developing spinal cord. 38 Furthermore, we uncover that these proteins restrict and moderate the expression of spinal 39 isoforms of Pou2f2, a transcription factor known to regulate B-cell differentiation. By gain-40 or loss-of-function experiments, we show that Pou2f2 contribute to regulate the position of 41 V2 populations in the developing spinal cord. Thus, we uncovered a genetic pathway that 42 regulates the diversification and the distribution of V2 interneurons during embryonic 43 development. 44 45 46 Significance statement 47 In this study, we identify the Onecut and Pou2f2 transcription factors as regulators of spinal 48 interneuron diversification and migration, two events that are critical for proper CNS 49 development. 50 51

Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord

“…V2a interneurons have recently been shown to consist of two major subgroups that have different settling positions: a medial subgroup expressing Nfib and Neurod2 and a lateral subgroup that expresses Shox2 and Zfhx3 (Hayashi et al, 2018). Furthermore, the lateral subgroup seems to further diversify into subgroups labelled by Shox2 and Maf/Onecut TFs (Francius et al, 2013;Harris et al, 2018). Consistent with this, hierarchical clustering of the single cell transcriptome data revealed four major subtypes of V2a neurons ( Fig 4D).…”

Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord

“…V2a interneurons have recently been shown to consist of two major subgroups that have different settling positions: a medial subgroup that expresses Nfib and Neurod2, and a lateral subgroup that expresses Shox2 and Zfhx3 (Hayashi et al, 2018). Furthermore, the lateral subgroup appears to diversify further into subgroups that are labelled by Shox2 and Maf/onecut family TFs (Francius et al, 2013; Harris et al, 2018 preprint). Consistent with this, hierarchical clustering of the single cell transcriptome data revealed four major subtypes of V2a neurons (Fig.…”

Temporal patterning of the central nervous system by a shared transcription factor code

“…Onecut TFs, for example, are required in early-born V1 and MNs for the specification of Renshaw cells and medial lateral motor column (LMCm) neurons respectively (Roy et al, 2012; Stam et al, 2012). Furthermore, Onecut TFs and Pou2f2 control the distribution of neurons from multiple dorsal-ventral domains (Harris et al, 2019; Kabayiza et al, 2017; Masgutova et al, 2019). Neurod2/6 control neuropeptide expression in inhibitory neurons in the dorsal horns of the spinal cord (Bröhl et al, 2008) and characterization of V2a neuron heterogeneity revealed that Zfhx3 and Neurod2/Nfib divide this neuronal class into a lateral and medial population (Hayashi et al, 2018).…”