Journal
DEVELOPMENT
Volume 139, Issue 17, Pages 3109-3119Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.078501
Keywords
Onecut factors; Isl1; Sip1; Neuronal diversification; Spinal cord; CNS development
Categories
Funding
- NICHD
- Universite catholique de Louvain
- Credit au chercheur [1.5.085.10.F]
- Fund for Scientific Medical Research of the Fonds de la Recherche Scientifique-FNRS [3.4.538.10.F]
- Actions de Recherche Concertees (Communaute francaise de Belgique and Academie Louvain) [10/15-026]
- Research Council of KU Leuven [OT-09/053, GOA-11/012]
- Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO-V) [G.0954.11N]
- Queen Elisabeth Medical Foundation [GSKE 1113]
- Hercules Foundation
- Deutsche Forschungsgemeinschaft (DFG)
- Fonds pour la formation a la Recherche dans l'Industrie et dans l'Agriculture (F.R.I.A., Belgium)
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During development, spinal motoneurons (MNs) diversify into a variety of subtypes that are specifically dedicated to the motor control of particular sets of skeletal muscles or visceral organs. MN diversification depends on the coordinated action of several transcriptional regulators including the LIM-HD factor Isl1, which is crucial for MN survival and fate determination. However, how these regulators cooperate to establish each MN subtype remains poorly understood. Here, using phenotypic analyses of single or compound mutant mouse embryos combined with gain-of-function experiments in chick embryonic spinal cord, we demonstrate that the transcriptional activators of the Onecut family critically regulate MN subtype diversification during spinal cord development. We provide evidence that Onecut factors directly stimulate Isl1 expression in specific MN subtypes and are therefore required to maintain Isl1 production at the time of MN diversification. In the absence of Onecut factors, we observed major alterations in MN fate decision characterized by the conversion of somatic to visceral MNs at the thoracic levels of the spinal cord and of medial to lateral MNs in the motor columns that innervate the limbs. Furthermore, we identify Sip1 (Zeb2) as a novel developmental regulator of visceral MN differentiation. Taken together, these data elucidate a comprehensive model wherein Onecut factors control multiple aspects of MN subtype diversification. They also shed light on the late roles of Isl1 in MN fate decision.
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