A major cause of chronic disability in neonates is diffuse white matter injury (DWMI) and hypomyelination. Altered
development of the WM is directly associated with adverse outcomes, including cerebral palsy, cognitive delay
and neurobehavioral abnormalities. The cellular pathophysiology underlying DWMI and defective myelination is
complex and not fully understood. Our lab has extensively published on the effects of neonatal brain injury on
white matter development, and demonstrated that OL progenitor cells (OPCs) display delayed maturation into
OLs, which results in aberrant myelination, altered WM function and behavioral abnormalities.
In the postnatal and adult brain, OPCs arise from radial glial cells (RGCs) of the subventricular zone (SVZ),
a major gliogenic and neurogenic region of the brain. OPC proliferate in the SVZ and migrate throughout the
brain to gray and WM, where they mature into myelinating OLs. While some important signaling pathways have
been characterized, much remains unknown about homeostatic regulation of OPC proliferation and maturation
in the SVZ, both during normal development and after injury. Furthermore, although it is established that the
proliferative response of endogenous OPCs to injury is crucial for expanding this progenitor pool and for
regenerating a normal number of OLs, the endogenous molecular signals involved in the regulation of OPC
proliferation in the SVZ are still largely undefined.
We utilized our previously generated Endothelin-1 (ET-1) and ET-1 receptor (Ednr) mouse mutant lines, and
discovered that, in the postnatal brain, RGC-derived ET-1 plays a novel and different role, i.e. regulates OPC
proliferation. In this proposal, we will test the hypothesis that ET-1 signaling between RGCs and OPCs plays
a crucial role in SVZ developmental homeostasis and regeneration. We will use an integrated approach in
a mouse model and in a larger mammal (piglet), in which the SVZ displays a structure and a cellular composition
identical to the human brain. Firstly, we will define the role of RGC-derived ET-1 and specific Ednr(s) in SVZ
OPC proliferation in mouse and piglet during normal development. Secondly, we will determine the role of ET-1
in OPC proliferation and differentiation after HX. Finally, we will define the molecular pathways involved in HX-
induced alterations in SVZ OPCs, in particular genes that are downstream of Ednr activation and are involved in
OPC proliferation, cell-cycle exit and cell differentiation. Together, these studies will not only shed light on crucial
cellular mechanisms of HX-induced delay in WM maturation, but might also lead to the development of new
therapeutic approaches aimed at lessening the long-term neurological sequelae of HX-induced neonatal brain
injury.
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