Self-renewing and differentiating properties of cortical neural stem cells are selectively regulated by basic fibroblast growth factor (FGF) signaling via specific FGF receptors
Self-renewing and differentiating properties of cortical neural stem cells are selectively regulated by basic fibroblast growth factor (FGF) signaling via specific FGF receptors
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DOI：
10.1523/jneurosci.5141-06.2007
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发表时间：
2007-02-21
影响因子：
5.3
通讯作者：
Barker, Jeffery L.
中科院分区：
文献类型：
--
作者：
Maric, Dragan;Pla, Alessandra Fiorio;Barker, Jeffery L.
由于从直接或间接来源于神经干细胞的增殖性谱系限制祖细胞（LRP）中鉴定真正的神经干细胞的持续模糊性，介导自自我更新神经干细胞（NSCs）开始谱系定型的发育过程仍不清楚。我们的多谱系免疫组化分析早期胚胎大鼠端脑在神经发生的发病揭示了明确的背腹梯度出现两种类型的神经元祖细胞（NP）从多谱系阴性的神经干细胞。使用全面的流式细胞术分析的NSC计数表明，它们在体内的急剧下降涉及到积极分化成NP和增加的凋亡倾向。这两个过程都抑制了成纤维细胞生长因子受体（FGFR）表达的背腹变化。位于端脑背侧的神经干细胞共表达FGFR 1和FGFR 3，而位于端脑腹侧的神经干细胞也表达FGFR 2。神经干细胞暴露于碱性成纤维细胞生长因子（bFGF）在体外产生四个刻板的克隆扩增状态：有效的自我更新，低效的自我更新有限的细胞凋亡，完全神经原性，和多潜能，产生多达五种类型的LRP。这些扩展状态之间的可塑性依赖于周围[bFGF]，端脑发育阶段，和特定的FGFRs的差异激活/失活。FGFR 1和FGFR 3的共激活促进了神经干细胞的对称分裂（自我更新），而失活则触发了这些细胞的不对称分裂和神经发生。FGFR 2表达的发育上调与神经干细胞向多能状态或凋亡的转变相关。这些结果提供了新的见解FGFRs在NSC特性的多样化和神经谱系限制性分化的启动中的作用。
Developmental processes mediating the initiation of lineage commitment from self-renewing neural stem cells (NSCs) remain mostly unclear because of the persisting ambiguity in identifying true NSCs from proliferative lineage-restricted progenitors (LRPs), which are directly or indirectly derived from NSCs. Our multilineage immunohistochemical analyses of early embryonic rat telencephalon at the onset of neurogenesis revealed clear dorsoventral gradients in the emergence of two types of neuronal progenitors (NPs) from multilineage-negative NSCs. Enumeration of NSCs using comprehensive flow cytometric analysis demonstrated that their precipitous decline in vivo involved both active differentiation into NPs and an increased propensity toward apoptosis. Both processes paralleled the dorsoventral changes in fibroblast growth factor receptor (FGFR) expressions. NSCs residing in the dorsal telencephalon coexpressed FGFR1 and FGFR3, whereas those residing in the ventral telencephalon also expressed FGFR2. NSCs exposed to basic fibroblast growth factor (bFGF) in vitro generated four stereotypical clonal expansion states: efficiently self-renewing, inefficiently self-renewing limited by apoptosis, exclusively neurogenic, and multipotential, generating up to five types of LRPs. The plasticity among these expansion states depended on ambient [bFGF], telencephalic developmental stage, and differential activation/inactivation of specific FGFRs. Coactivation of FGFR1 and FGFR3 promoted symmetrical divisions of NSCs (self-renewal), whereas inactivation of either triggered asymmetrical divisions and neurogenesis from these cells. Developmental upregulation of FGFR2 expression correlated with a shift of NSCs into a multipotential state or apoptosis. These results provide new insights regarding the roles of FGFRs in diversification of NSC properties and initiation of neural lineage-restricted differentiation.