Yun Kyuson, Fischman Seth, Johnson Jane, Hrabe de Angelis Martin, Weinmaster Gerry, Rubenstein John L R
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, LPPI, University of California, San Francisco, 401 Parnassus, Box 0984, 94143-0984, USA.
Development. 2002 Nov;129(21):5029-40. doi: 10.1242/dev.129.21.5029.
Notch signaling has a central role in cell fate specification and differentiation. We provide evidence that the Mash1 (bHLH) and Dlx1 and Dlx2 (homeobox) transcription factors have complementary roles in regulating Notch signaling, which in turn mediates the temporal control of subcortical telencephalic neurogenesis in mice. We defined progressively more mature subcortical progenitors (P1, P2 and P3) through their combinatorial expression of MASH1 and DLX2, as well as the expression of proliferative and postmitotic cell markers at E10.5-E11.5. In the absence of Mash1, Notch signaling is greatly reduced and 'early' VZ progenitors (P1 and P2) precociously acquire SVZ progenitor (P3) properties. Comparing the molecular phenotypes of the delta-like 1 and Mash1 mutants, suggests that Mash1 regulates early neurogenesis through Notch-and Delta-dependent and -independent mechanisms. While Mash1 is required for early neurogenesis (E10.5), Dlx1 and Dlx2 are required to downregulate Notch signaling during specification and differentiation steps of 'late' progenitors (P3). We suggest that alternate cell fate choices in the developing telencephalon are controlled by coordinated functions of bHLH and homeobox transcription factors through their differential affects on Notch signaling.
Notch信号通路在细胞命运决定和分化过程中起着核心作用。我们提供的证据表明，Mash1（bHLH）以及Dlx1和Dlx2（同源框）转录因子在调节Notch信号通路中具有互补作用，而Notch信号通路反过来介导了小鼠皮质下端脑神经元发生的时间控制。我们通过MASH1和DLX2的组合表达，以及在E10.5 - E11.5时增殖和有丝分裂后细胞标志物的表达，定义了逐渐成熟的皮质下祖细胞（P1、P2和P3）。在缺乏Mash1的情况下，Notch信号通路大幅减少，“早期”脑室区祖细胞（P1和P2）过早获得了脑室下区祖细胞（P3）的特性。比较delta样1和Mash1突变体的分子表型表明，Mash1通过Notch依赖性和非依赖性机制以及Delta依赖性和非依赖性机制调节早期神经发生。虽然早期神经发生（E10.5）需要Mash1，但在“晚期”祖细胞（P3）的特化和分化步骤中，Dlx1和Dlx2是下调Notch信号通路所必需的。我们认为，发育中的端脑中不同的细胞命运选择是由bHLH和同源框转录因子通过它们对Notch信号通路的不同影响而产生的协同作用所控制的。
