Research over the past few decades has greatly expanded our knowledge of the processes contributing to cellular diversity in the embryonic and adult central nervous system. However, little is known about the basic processes underlying the formation of the human brainstem, particularly during the pediatric period. This time during brain development is of particular interest to pediatric neurosurgeons, neuro-oncologists, and the public at large, given the relatively high incidence of brainstem tumors in the pediatric population as compared to adults and the dismal prognosis associated with these tumors. Given the mounting evidence that primary brain tumors may arise from specific stem cell populations, a more complete understanding of the cellular organization and molecular processes underlying brainstem formation in children would greatly contribute to our understanding of not only normal brain development but also pediatric tumor biology. Preliminary studies from our laboratory have identified proliferating populations of neural progenitors in the developing pons. However, little is known regarding the contribution of such progenitor populations to brainstem histogenesis and basic processes underlying cellular diversity in this important brain region. We hypothesize that discrete spatially and temporally defined neural stem cell populations are responsible for cellular diversity in the developing brainstem. Through the analysis of archived pediatric human tissue, we aim to establish the anatomic location and temporal profiles of these stem cell populations in the pediatric human brainstem. In addition, we propose to expand these experiments into a mouse system to characterize in detail the basic properties and eventual destination of cells born in these germinal regions. These studies in combination will provide new insights into the fundamental steps governing brainstem formation and provide a foundation for future studies aimed at elucidating the molecular events leading to development of brainstem tumors. PUBLIC HEALTH RELEVANCE: Pediatric brainstem tumors harbor a poor prognosis and are the leading cause of cancer-related death from brain tumors in children, which is related to its invasive nature, inaccessibility to surgical intervention, and resistance to medical therapy. Currently, little is known about the fundamental steps governing brainstem formation and tumorigenesis. In this proposal, we aim to understand the basic processes underlying human brainstem formation, which will provide a foundation for future studies aimed at elucidating the molecular events leading to development of brainstem tumors and for the development of novel treatment strategies for this deadly disease.