Jagged2 controls the generation of motor neuron and oligodendrocyte progenitors in the ventral spinal cord

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Abstract

In the developing spinal cord, motor neurons (MNs) and oligodendrocytes arise sequentially from a common pool of progenitors. However, the genetic network responsible for this neurogenesis to gliogenesis switch is largely unknown. A transcriptome analysis identified the Notch ligand Jagged2 (JAG2) as a Sonic hedgehog-regulated factor transiently expressed in MN progenitors (pMNs). In vivo loss- and gain-of-function experiments show that JAG2 schedules the differentiation of the pMN progenitors. At early developmental stages, Olig2 expressing pMN progenitors that enter the differentiation pathway exclusively generate MNs. At these times, the activation of the Notch pathway by JAG2 maintains selected pMN progenitors in an undifferentiated state by two mechanisms; first it inhibits MN generation by reducing Olig2 proteins levels, and second it directly inhibits the premature generation of oligodendrocyte progenitors (OLPs) by maintaining high levels of Hes5. Later, extinction of JAG2 from the pMN results in the loss of Hes5 expression, heralding the gliogenic phase of pMN progenitors. Strikingly, downregulation of JAG2 in pMN progenitors is sufficient to promote the precocious generation of OLPs. Together these data provide evidence that JAG2 is a key regulator of the timely and ordered generation of two of the defining cell types in the spinal cord, MNs and OLPs.