VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium.
VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium; Program in Molecular and Developmental Genetics, Doctoral School for Biomedical Sciences, University of Leuven School Group Biomedicine, 3000 Leuven, Belgium.
Cell. 2016 Jan 28;164(3):460-75. doi: 10.1016/j.cell.2015.12.048.
Neurogenesis is initiated by the transient expression of the highly conserved proneural proteins, bHLH transcriptional regulators. Here, we discover a conserved post-translational switch governing the duration of proneural protein activity that is required for proper neuronal development. Phosphorylation of a single Serine at the same position in Scute and Atonal proneural proteins governs the transition from active to inactive forms by regulating DNA binding. The equivalent Neurogenin2 Threonine also regulates DNA binding and proneural activity in the developing mammalian neocortex. Using genome editing in Drosophila, we show that Atonal outlives its mRNA but is inactivated by phosphorylation. Inhibiting the phosphorylation of the conserved proneural Serine causes quantitative changes in expression dynamics and target gene expression resulting in neuronal number and fate defects. Strikingly, even a subtle change from Serine to Threonine appears to shift the duration of Atonal activity in vivo, resulting in neuronal fate defects.
神经发生是由高度保守的神经前体细胞蛋白的瞬时表达所引发的，这些蛋白是 bHLH 转录调节因子。在这里，我们发现了一个保守的翻译后开关，它控制着神经前体细胞蛋白活性的持续时间，这对于正常的神经元发育是必需的。在 Scute 和 Atonal 神经前体细胞蛋白中，同一位置的单个丝氨酸的磷酸化通过调节 DNA 结合，调控从活性到非活性形式的转变。发育中的哺乳动物新皮层中，Neurogenin2 的等效苏氨酸也调节 DNA 结合和神经前体细胞活性。我们利用果蝇中的基因组编辑表明，Atonal 的 mRNA 寿命较长，但通过磷酸化失活。抑制保守神经前体细胞丝氨酸的磷酸化会导致表达动力学和靶基因表达的定量变化，从而导致神经元数量和命运缺陷。引人注目的是，即使是 Ser 到 Thr 的微小变化似乎也会改变 Atonal 在体内的活性持续时间，导致神经元命运缺陷。
