Duchenne Muscular Dystrophy (DMD) results from mutations in the dystrophin gene, but since DMD patients can present with cognitive and behavioral disorders, there is a need to understand dystrophin in neurodevelopment.

Although the dystrophin gene produces various isoforms, only the largest isoform, Dp427, is well understood, as it links the extracellular matrix and the cytoskeleton in skeletal muscle. Yet nearly one-third of DMD patients present with serious cognitive impairment of which the severity is correlated with the successive loss of smaller dystrophin isoforms.  MRI studies have demonstrated that DMD patients have smaller gray matter volumes, higher white matter diffusivity, and lower fractional anisotropy, with mutations that affected the expression of Dp140 contributing the most to gray matter volume differences.

The timing and proper execution of myelination plays a critical role in neurological processes. The ventricular/subventricular zone (V-SVZ), the largest neural stem cell (NSC) niche in the adult mammalian brain, generates the majority of oligodendrocyte progenitor cells (OPCs) that will myelinate the forebrain. Ependymal cells (ECs) are specialized multi-ciliated cells that establish a pinwheel arrangement around NSCs, which is critical to establish the V-SVZ microenvironment that supports regulated NSC activation. First, we will use postnatal V-SVZ wholemounts to examine the NSC niche architecture in DMD mouse models. Second, we will examine the output of the neonatal V-SVZ by examining OPCs and key steps in generating myelinating oligodendrocytes.

Dystrophin isoform expression is developmentally regulated in the postnatal V-SVZ. We found Dp140 and Dp71 transcripts at high levels from P3-P14, a critical period in the development of the neonatal V-SVZ.

By exploring the hypothesis that dystrophin critically contributes to building the early postnatal V-SVZ niche, we will elucidate potential cellular mechanisms underlying the neurological deficits in DMD patients.