Graduate Program in Molecular and Developmental Biology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Dev Biol. 2021 Aug;476:137-147. doi: 10.1016/j.ydbio.2021.03.019. Epub 2021 Mar 26.
The MAPK pathway is a major growth signal that has been implicated during the development of progenitors, neurons, and glia in the embryonic brain. Here, we show that the MAPK pathway plays an important role in the generation of distinct cell types from progenitors in the ventral telencephalon. Our data reveal that phospho-p44/42 (called p-ERK1/2) and the ETS transcription factor Etv5, both downstream effectors in the MAPK pathway, show a regional bias in expression during ventral telencephalic development, with enriched expression in the dorsal region of the LGE and ventral region of the MGE at E13.5 and E15.5. Interestingly, expression of both factors becomes more uniform in ventricular zone (VZ) progenitors by E18.5. To gain insight into the role of MAPK activity during progenitor cell development, we used a cre inducible constitutively active MEK1 allele (Rosa) in combination with a ventral telencephalon enriched cre (Gsx2e-cre) or a dorsal telencephalon enriched cre (Emx1). Sustained MEK/MAPK activity in the ventral telencephalon (Gsx2e-cre; Rosa) expanded dorsal lateral ganglionic eminence (dLGE) enriched genes (Gsx2 and Sp8) and oligodendrocyte progenitor cell (OPC) markers (Olig2, Pdgfrα, and Sox10), and also reduced markers in the ventral (v) LGE domain (Isl1 and Foxp1). Activation of MEK/MAPK activity in the dorsal telencephalon (Emx1; Rosa) did not initially activate the expression of dLGE or OPC genes at E15.5 but ectopic expression of Gsx2 and OPC markers were observed at E18.5. These results support the idea that MAPK activity as readout by p-ERK1/2 and Etv5 expression is enriched in distinct subdomains of ventral telencephalic progenitors during development. In addition, sustained activation of the MEK/MAPK pathway in the ventral or dorsal telencephalon influences dLGE and OPC identity from progenitors.
MAPK 途径是一种主要的生长信号，在胚胎大脑中祖细胞、神经元和神经胶质的发育过程中被牵涉。在这里，我们表明 MAPK 途径在从腹侧端脑祖细胞中产生不同类型的细胞中发挥重要作用。我们的数据表明，磷酸化 p44/42（称为 p-ERK1/2）和 ETS 转录因子 Etv5，这两者都是 MAPK 途径的下游效应物，在腹侧端脑发育过程中表现出区域表达偏向，在 E13.5 和 E15.5 时在 LGE 的背侧区域和 MGE 的腹侧区域富集表达。有趣的是，到 E18.5 时，这两种因子在脑室区（VZ）祖细胞中的表达变得更加均匀。为了深入了解 MAPK 活性在祖细胞发育过程中的作用，我们使用了一个可诱导的组成型活性 MEK1 等位基因（Rosa），与一个腹侧端脑富集的 cre（Gsx2e-cre）或一个背侧端脑富集的 cre（Emx1）结合。在腹侧端脑（Gsx2e-cre；Rosa）中持续的 MEK/MAPK 活性扩展了背外侧神经节隆起（dLGE）富集基因（Gsx2 和 Sp8）和少突胶质前体细胞（OPC）标记物（Olig2、Pdgfrα 和 Sox10），并减少了 vLGE 结构域中的标记物（Isl1 和 Foxp1）。在背侧端脑（Emx1；Rosa）中激活 MEK/MAPK 活性在 E15.5 时最初不会激活 dLGE 或 OPC 基因的表达，但在 E18.5 时观察到 Gsx2 和 OPC 标记物的异位表达。这些结果支持这样的观点，即作为 p-ERK1/2 和 Etv5 表达的读出的 MAPK 活性在发育过程中在腹侧端脑祖细胞的不同亚域中富集。此外，在腹侧或背侧端脑持续激活 MEK/MAPK 途径会影响来自祖细胞的 dLGE 和 OPC 特性。
