Project

Fetal microglia aid in defining the proliferative zones of neural stem cells in the developing cerebral cortex?

Neurodevelopmental disorders, in general, and particularly autism and schizophrenia are associated with altered brain organization and structure resulting as a consequence of aberrant neurogenesis. Embryonic neurogenesis is a rapid process, resulting in the production of billions of neurons over a short period of time from the multipotent neural progenitor cells. Neurogenesis, therefore, needs to be carefully regulated to ensure the right balance between cell production and the requirements of the growing cerebral cortex. Yet, the precise mechanism by which the precursor cell production is restrained and regulated during cortical neurogenesis still remains unclear. The neural stem cells in the fetal forebrain are localized in the ventricular zone (VZ) and the subventricular zone (SVZ), the two proliferative zones where they divide to give rise to daughter neuronal cells. We have shown that microglia colonize the fetal cortex during development and regulate the number of neural and glial stem cells in the fetal brain through phagocytosis. The goal of the study was to better understand the role of microglial cells in regulating the neural stem cell pool during neocortical development. Preliminary evidence from macaque occipital coronal sections shows that microglia are positioned as a monolayer at the interface between the VZ and SVZ. Based on this finding, we hypothesized that microglia phagocytose neural stem cells at the boundaries between the VZ and SVZ and thus, microglia may help define proliferative zones of neural stem cells by culling those cells that migrate beyond specified boundaries. To investigate this possibility, the distribution of fetal microglial cells in coronal brain sections isolated from rat (Sprague-Dawley), macaque (Macaca mulatta) and chicken (Gallus gallus domesticus) animal models at different stages of fetal brain development were analyzed. In confirmation of the preliminary results, microglia were noted to often position themselves at the border between the VZ and SVZ proliferative zones, a phenomena conserved across all the three species analyzed, thereby suggesting an evolutionary microglial patterning in the developing cortex. Moreover, the first evidence of the microglial cell line up at the interface in embryonic rat coincides with the age that reflects the peak of layer 3 neurogenesis, wherein overproduction of layer 3 neurons had been closely associated with the onset of autism like symptoms. However, with the lack of quantifiable evidence of higher proportion of microglial phagocytosis at the VZ/SVZ interface as compared to the other locations within the proliferative zones and co-labeling of microglia with markers of activated Iba1+ cells, our data remains inconclusive but definitely provides the first proof of concept towards our hypothesis and warrants future studies aimed in this direction.

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