Abstract
Author SummaryThe embryonic spinal cord is organized into an array of discrete neural progenitor domains along the dorsoventral axis. Most of these domains undergo two periods of differentiation, first producing specific classes of neurons and then generating distinct populations of glial cells at later times. In addition, each of these progenitors pools exhibit marked differences in their proliferative capacities and propensity to differentiate to produce the appropriate numbers and diversity of neurons and glia needed to form functional neural circuits. The mechanisms behind this regional control of neural progenitor behavior, however, remain unclear. In this study, we identify the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF) as a critical regulator of this process in the chick spinal cord. We show that PLZF is initially expressed by all spinal cord progenitors and then becomes restricted to a central domain, where it helps to limit the rate of neuronal differentiation and to preserve the progenitor pool for subsequent glial production. We also demonstrate that PLZF acts by promoting the expression of Fibroblast Growth Factor (FGF) Receptor 3, thereby enhancing the proliferative response of neural progenitors to FGFs present in developing embryos. Together, these findings reveal a novel developmental strategy for spatially controlling neural progenitor behavior by tuning their responsiveness to broadly distributed growth-promoting signals in the embryonic environment.
Highlights
The formation of neural circuits within the developing central nervous system (CNS) depends upon the spatially and temporally ordered generation of distinct classes of neurons and glia from multipotent neural stem and progenitor cells (NPCs)
We show that Promyelocytic Leukemia Zinc Finger (PLZF) is initially expressed by all spinal cord progenitors and becomes restricted to a central domain, where it helps to limit the rate of neuronal differentiation and to preserve the progenitor pool for subsequent glial production
We demonstrate that PLZF acts by promoting the expression of Fibroblast Growth Factor (FGF) Receptor 3, thereby enhancing the proliferative response of neural progenitors to FGFs present in developing embryos
Summary
The formation of neural circuits within the developing central nervous system (CNS) depends upon the spatially and temporally ordered generation of distinct classes of neurons and glia from multipotent neural stem and progenitor cells (NPCs). An essential feature of this progression is the ability of NPCs to self-renew in a manner that permits early-born cells such as neurons to form while maintaining a sufficient progenitor pool to generate later-born cell types such as glia. At early stages of development, NPCs are broadly responsive to mitogenic stimulation. This responsiveness markedly changes over time and often becomes region-specific such that some groups of cells proliferate for protracted time periods while others rapidly differentiate [2,3]. While important for determining the size and shape of the developing CNS, the mechanisms underlying these differences in mitogen sensitivity remain poorly defined
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