Abstract
Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem cell self-renewal.
Highlights
A fundamental feature of neural development is the production of defined types of neurons in a temporal order from multipotent, regionally-specified neural stem and progenitor cells [1]
Too much self-renewal would result in a brain with too few neurons and abnormal circuitry; too much neurogenesis would deplete all of the neural stem cells too quickly, resulting in a small brain and neurological abnormalities
We used one transcription factor, Pax6, which is important for this decision, as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in the developing mouse brain
Summary
A fundamental feature of neural development is the production of defined types of neurons in a temporal order from multipotent, regionally-specified neural stem and progenitor cells [1]. During nervous system development, maintaining the balance between stem cell self-renewal and neurogenesis is essential for the generation of the correct proportions of different classes of neurons and subsequent circuit assembly. Little is known of the molecular control of the key neural stem (NS) cell properties of multipotency and self-renewal. Detailed analyses of neocortical and retinal development in mice mutant for Pax have identified defects in neural stem and progenitor cell proliferation, multipotency, neurogenesis, the generation of specific types of neurons, and marked changes in spatial pattern [8,9,10,11,12,13,14,15,16,17,18,19]. Loss of Pax function results in microcephaly, abnormal development of the secondary progenitor population of the subventricular zone (SVZ, known as basal progenitor cells, BP cells) and a disproportionate reduction in the production of later-born, upper layer neurons [12,14,15,17,20,21,22,23]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call