PLZF regulates fibroblast growth factor responsiveness and maintenance of neural progenitors.
PLZF regulates fibroblast growth factor responsiveness and maintenance of neural progenitors.
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DOI：
10.1371/journal.pbio.1001676
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发表时间：
2013-10
期刊：
影响因子：
9.8
通讯作者：
Novitch BG
中科院分区：
文献类型：
--
作者：
Gaber ZB;Butler SJ;Novitch BG
一种称为早幼粒细胞白血病锌指 (PLZF) 的转录因子通过增强脊髓祖细胞对发育胚胎中存在的有丝分裂原的敏感性来校准脊髓祖细胞维持和分化之间的平衡。发育中的脊髓中不同类别的神经元和神经胶质细胞在特定时间以特定数量从空间上离散的神经祖细胞域产生。因此，相邻结构域的增殖潜力和分化时间可能表现出显着差异。然而，人们对这种区域控制的机制知之甚少。在这里，我们发现转录因子早幼粒细胞白血病锌指 (PLZF) 通过门控成纤维细胞生长因子 (FGF) 受体 3 的表达和祖细胞对 FGF 的反应，在塑造神经元分化模式中发挥着关键作用。 PLZF 升高会增加 FGFR3 表达和 STAT3 通路活性，抑制神经发生，并使祖细胞偏向于神经胶质细胞的产生。相反，PLZF 缺失会降低 FGFR3 水平，导致神经元过早分化。总之，这些发现揭示了一种新的转录策略，用于在空间上调整不同神经祖细胞群对胚胎环境中广泛分布的有丝分裂信号的反应性。胚胎脊髓沿背腹轴组织成一系列离散的神经祖细胞域。大多数这些域经历两个分化期，首先产生特定类别的神经元，然后在稍后的时间产生不同的神经胶质细胞群。此外，每个祖细胞库的增殖能力和分化倾向都表现出显着差异，以产生形成功能性神经回路所需的适当数量和多样性的神经元和神经胶质细胞。然而，这种神经祖细胞行为的区域控制背后的机制仍不清楚。在这项研究中，我们确定转录因子早幼粒细胞白血病锌指（PLZF）是雏鸡脊髓中这一过程的关键调节因子。我们发现 PLZF 最初由所有脊髓祖细胞表达，然后被限制在中央区域，在那里它有助于限制神经元分化的速度并保留祖细胞库以用于随后的神经胶质细胞的产生。我们还证明 PLZF 通过促进成纤维细胞生长因子 (FGF) 受体 3 的表达发挥作用，从而增强神经祖细胞对发育胚胎中存在的 FGF 的增殖反应。总之，这些发现揭示了一种新的发育策略，通过调整神经祖细胞对胚胎环境中广泛分布的生长促进信号的反应来空间控制神经祖细胞的行为。
A transcription factor called Promyelocytic Leukemia Zinc Finger (PLZF) calibrates the balance between spinal cord progenitor maintenance and differentiation by enhancing their sensitivity to mitogens that are present in developing embryos. Distinct classes of neurons and glial cells in the developing spinal cord arise at specific times and in specific quantities from spatially discrete neural progenitor domains. Thus, adjacent domains can exhibit marked differences in their proliferative potential and timing of differentiation. However, remarkably little is known about the mechanisms that account for this regional control. Here, we show that the transcription factor Promyelocytic Leukemia Zinc Finger (PLZF) plays a critical role shaping patterns of neuronal differentiation by gating the expression of Fibroblast Growth Factor (FGF) Receptor 3 and responsiveness of progenitors to FGFs. PLZF elevation increases FGFR3 expression and STAT3 pathway activity, suppresses neurogenesis, and biases progenitors towards glial cell production. In contrast, PLZF loss reduces FGFR3 levels, leading to premature neuronal differentiation. Together, these findings reveal a novel transcriptional strategy for spatially tuning the responsiveness of distinct neural progenitor groups to broadly distributed mitogenic signals in the embryonic environment. The 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.
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