Nian Fang-Shin, Liao Bo-Kai, Su Yen-Lin, Wu Pei-Rong, Tsai Jin-Wu, Hou Pei-Shan
Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
Mol Neurobiol. 2025 Apr;62(4):4076-4092. doi: 10.1007/s12035-024-04530-9. Epub 2024 Oct 11.
Notch signaling plays a pivotal role in regulating various developmental processes, particularly in controlling the timing of neuronal production within the developing neocortex. Central to this regulatory mechanism is the oscillatory pattern of Delta, which functions as a developmental clock modulator. Its deficiency profoundly impairs mammalian brain formation, highlighting its fundamental role in brain development. However, zebrafish carrying a mutation in the functional ortholog DeltaC (dlc) within their functional ortholog exhibit an intact forebrain structure, implying evolutionary variations in Notch signaling within the forebrain. In this study, we unveil the distinct yet analogous expression profiles of Delta and Her genes in the developing vertebrate forebrain. Specifically, for the first time, we detected the oscillatory expression of the Delta gene dlc in the developing zebrafish forebrain. Although this oscillatory pattern appeared irregular and was not pervasive among the progenitor population, attenuation of the dlc-involved Notch pathway using a γ-secretase inhibitor impaired neuronal differentiation in the developing zebrafish forebrain, revealing the indispensable role of the dlc-involved Notch pathway in regulating early zebrafish neurogenesis. Taken together, our results demonstrate the foundational prototype of dlc-involved Notch signaling in the developing zebrafish forebrains, upon which the intricate patterns of the mammalian neocortex may have been sculpted.
Notch信号通路在调节各种发育过程中起着关键作用，尤其是在控制发育中的新皮层内神经元产生的时间方面。这种调节机制的核心是Delta的振荡模式，它作为一种发育时钟调节剂发挥作用。其缺陷会严重损害哺乳动物的脑形成，突出了其在脑发育中的基本作用。然而，在其功能直系同源物中携带功能性直系同源物DeltaC（dlc）突变的斑马鱼表现出完整的前脑结构，这意味着前脑内Notch信号通路存在进化差异。在本研究中，我们揭示了Delta和Her基因在发育中的脊椎动物前脑中不同但类似的表达谱。具体而言，我们首次在发育中的斑马鱼前脑中检测到Delta基因dlc的振荡表达。尽管这种振荡模式看起来不规则且在祖细胞群体中并不普遍，但使用γ-分泌酶抑制剂减弱涉及dlc的Notch信号通路会损害发育中的斑马鱼前脑的神经元分化，揭示了涉及dlc的Notch信号通路在调节斑马鱼早期神经发生中的不可或缺的作用。综上所述，我们的结果证明了在发育中的斑马鱼前脑中涉及dlc的Notch信号的基础原型，哺乳动物新皮层的复杂模式可能就是在此基础上塑造而成的。
