Targets and mechanisms of action of the Onecut transcription factors during spinal motor neuron diversification

The locomotion is coordinated by complex neuronal networks, called Central Pattern Generators. These circuits are located in the ventral part of the spinal cord, and they are composed of motor neurons and of interneurons. During the embryonic development, motor neurons diversify into different subsets characterized by a distinct molecular identity, localization and connectivity. However, although the master genetic regulators that enable the development of motor neurons have been largely studied, the complete genetic programs are far to be fully deciphered. Previous data obtained in the laboratory have shown that the Onecut transcription factors are present in motor neurons where they directly regulate the expression of the Isl1 gene, a specific determinant of motor neurons, during the specification of these cells. However, the mechanisms of action by which Onecut factors regulate Isl1 expression remain unknown. Furthermore, other targets of Onecut factors in motor neurons remain to be elucidated. In this work, we provide evidence that CBP and p300 coactivators cooperate with Onecut factors to maintain Isl1 expression in postmitotics motor neurons. Moreover, we highlight that the Onecut factors oppositely control the expression of Nkx6.2 in V2 interneurons and in motor neurons. We also show that Nkx6.2 is required for proper development of the locomotor circuits. Thus, we uncover mechanisms of action of Onecut factors in the regulation of Isl1 expression and we identify Nkx6.2 as a downstream target of Onecut factors involved in the development of the spinal locomotor circuits.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201