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Sci Rep. 2020 Jan 22;10(1):996. doi: 10.1038/s41598-020-57945-4.

Onecut-dependent Nkx6.2 transcription factor expression is required for proper formation and activity of spinal locomotor circuits.

Author information

1
Université catholique de Louvain, Institute of Neuroscience, Laboratory of Neural Differentiation, Brussels, Belgium.
2
Université catholique de Louvain, Institute of Neuroscience, Laboratory of Cell Physiology, Brussels, Belgium.
3
Laboratory for Neural Development and Optical Recording (NDEVOR), Section for Physiology, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
4
Norwegian Center for Stem Cell Research, Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway.
5
Université catholique de Louvain, de Duve Institute, Flow cytometry and cell sorting facility (CYTF), Brussels, Belgium.
6
CIBER de Salud Mental (CIBERSAM), Madrid, Spain.
7
University of Cadiz, Cadiz, Spain.
8
Wayne state University, Center for Molecular Medicine and Genetics, Carman and Ann Adams Department of Pediatrics, Department of Neurology, Detroit, Michigan, USA.
9
Université catholique de Louvain, Institute of Neuroscience, Laboratory of Developmental Neurobiology, Brussels, Belgium.
10
Université catholique de Louvain, Institute of Neuroscience, Laboratory of Neural Differentiation, Brussels, Belgium. frederic.clotman@uclouvain.be.

Abstract

In the developing spinal cord, Onecut transcription factors control the diversification of motor neurons into distinct neuronal subsets by ensuring the maintenance of Isl1 expression during differentiation. However, other genes downstream of the Onecut proteins and involved in motor neuron diversification have remained unidentified. In the present study, we generated conditional mutant embryos carrying specific inactivation of Onecut genes in the developing motor neurons, performed RNA-sequencing to identify factors downstream of Onecut proteins in this neuron population, and employed additional transgenic mouse models to assess the role of one specific Onecut-downstream target, the transcription factor Nkx6.2. Nkx6.2 expression was up-regulated in Onecut-deficient motor neurons, but strongly downregulated in Onecut-deficient V2a interneurons, indicating an opposite regulation of Nkx6.2 by Onecut factors in distinct spinal neuron populations. Nkx6.2-null embryos, neonates and adult mice exhibited alterations of locomotor pattern and spinal locomotor network activity, likely resulting from defective survival of a subset of limb-innervating motor neurons and abnormal migration of V2a interneurons. Taken together, our results indicate that Nkx6.2 regulates the development of spinal neuronal populations and the formation of the spinal locomotor circuits downstream of the Onecut transcription factors.

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