Retinoic Acid Is Required for Oligodendrocyte Precursor Cell Production and Differentiation in the Postnatal Mouse Corpus Callosum
Morrison, Vivianne Eleanor
Huang, Jeffrey K
Maguire-Zeiss, Kathleen A
Myelination of the central nervous system (CNS) relies on the production of oligodendrocytes (OLs) from oligodendrocyte precursor cells (OPCs). During the first month of postnatal life, OPCs that eventually populate the corpus callosum arise from neural stem cells (NSCs) in the subventricular zone (SVZ) of the lateral ventricle and then mature to generate myelinating OLs. This process has been shown to require sonic hedgehog (SHH) signaling, but the extent of signals that regulate the production and maturation of OPCs in this region is not fully understood.Retinoic acid (RA) is a transcriptional regulator that works with SHH to control embryonic morphogenesis and contributes to remyelination following CNS injury. It is not known if RA promotes myelination of the normal developing brain, and the goal of this dissertation is to determine whether RA plays a role in the development of OLs and myelination in the early postnatal period.Here, we show that the RA-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2) is needed for the production and maturation of postnatal OPCs in the corpus callosum. Deletion of RALDH2 in neural/glial antigen 2-positive (NG2+) perivascular cells using a Ng2-Cre:Raldh2flox/flox mouse line reduced total OL lineage cell number, disrupted OPC differentiation, and caused hypomyelination of the corpus callosum in early postnatal life and into adulthood. The corpus callosum of knockout mice displayed significant histopathology, including alterations in myelin, axons, and astrocytes.Moreover, decreased OL lineage cell numbers coincided with reduced NSC survival and decreased SHH signaling in the SVZ. Additionally, the development of astrocytes was altered, and a reduction in deep layer neurons and a concomitant increase in upper layer neurons were observed, as well as decreased cortical thickness.Critically, our mouse model allows us to conclude that paracrine RA signaling between NG2+ perivascular cells and neural cell types is responsible for these phenomena in the normally developing postnatal mouse forebrain. Overall, this dissertation shows that RA continues to have a critical role in brain function in the postnatal period and that interactions between neural and non-neural cell types is integral to normal development.
Showing items related by title, author, creator and subject.
TRANSGENERATIONAL INHERITANCE OF INCREASED BREAST CANCER RISK IN MOUSE OFFSPRING OF DAMS EXPOSED TO HIGH FAT N-6 POLYUNSATURATED FATTY ACID DIET DURING PREGNANCY Nguyen, Nguyen (Georgetown University, 2017)Maternal high fat (HF) intake before and/or during pregnancy increases female offsprings’ mammary cancer risk in several preclinical models. Here I studied if maternal HF intake during pregnancy cause transgenerational ...