Theses Doctoral

Platelet-Derived Growth Factor Receptor Beta is a Marker and Regulator of Neural Stem Cells in the Adult Ventricular-Subventricular Zone

Maldonado-Soto, Angel Ricardo

Specific regions within the adult mammalian brain maintain the ability to generate neurons. The largest of these, the ventricular-subventricular zone (V-SVZ), comprises the entire lateral wall of the lateral ventricles. Here, a subset of glial fibrillary acid protein (GFAP)-positive astrocytes (B cells) gives rise to neurons and oligodendrocytes throughout life. This process of neurogenesis involves quiescent B cells becoming proliferative (epidermal growth factor receptor (EGFR)-positive) and giving rise to neuroblasts via transit amplifying precursors. The neuroblasts then migrate through the rostral migratory stream (RMS) to the olfactory bulbs (OBs), where they mature into neurons. Studying the stem cells in the V-SVZ has been hindered by the shortage of molecular markers to selectively target them. Using microarray and qPCR analysis of putative quiescent neural stem cells we determined that they were enriched for PDGFRβ mRNA. We used immunostaining to determine the in vivo identity of PDGFRβ+ cells, and discovered that only GFAP+ cells within the V-SVZ stem cell lineage express PDGFRβ. Moreover, these PDGFRβ+ B cells contact the ventricle at the center of ependymal pinwheel structures and the vast majority of them are EGFR-. Importantly, the V-SVZ/RMS/OBcore axis was highly enriched for PDGFRβ expression compared with other brain regions. Detailed morphological analyses of PDGFRβ+ B cells revealed primary cilia at their apical process in contact with the ventricle and long radial processes contacting blood vessels deep within the V-SVZ, both of which are characteristics of adult neural stem cells. When PDGFRβ+ cells were lineage traced in vivo they formed olfactory bulb neurons.
Using fluorescence-activated cell sorting (FACS) to purify PDGFRβ+ astrocytes we discovered this receptor is expressed by all adult V-SVZ neural stem cells, including a novel population of EGFR+ PDGFRβ+ cells which correspond to the activated neural stem cells. RNA-sequencing analysis of the purified populations revealed that PDGFRβ+ EGFR+ cells possess a transcriptional profile intermediate between quiescent neural stem cells and actively proliferating GFAP- progenitor cells. Finally, when PDGFRβ is deleted in adult GFAP+ NSCs we observe a decrease in EGFR+ and Dcx+ progenitor cells, together with an increase in quiescent GFAP+ astrocytes. A larger proportion of these mutant cells come in contact with the ventricular lumen, suggesting that PDGFRβ is required for V-SVZ astrocytes to act as stem cells, possibly by mediating interactions with their niche. Taken together, these data identify PDGFRβ as a novel marker for adult V-SVZ neural stem cells that is an important regulator of their stem cell capabilities.


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More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Doetsch, Fiona K.
Ph.D., Columbia University
Published Here
June 26, 2015