iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
Development. 2023 Oct 15;150(20). doi: 10.1242/dev.201152. Epub 2023 Jun 1.
Cell fate and growth require one-carbon units for the biosynthesis of nucleotides, methylation reactions and redox homeostasis, provided by one-carbon metabolism. Consistently, defects in one-carbon metabolism lead to severe developmental defects, such as neural tube defects. However, the role of this pathway during brain development and in neural stem cell regulation is poorly understood. To better understand the role of one carbon metabolism we focused on the enzyme Serine hydroxymethyl transferase (Shmt), a key factor in the one-carbon cycle, during Drosophila brain development. We show that, although loss of Shmt does not cause obvious defects in the central brain, it leads to severe phenotypes in the optic lobe. The shmt mutants have smaller optic lobe neuroepithelia, partly justified by increased apoptosis. In addition, shmt mutant neuroepithelia have morphological defects, failing to form a lamina furrow, which likely explains the observed absence of lamina neurons. These findings show that one-carbon metabolism is crucial for the normal development of neuroepithelia, and consequently for the generation of neural progenitor cells and neurons. These results propose a mechanistic role for one-carbon during brain development.
细胞命运和生长需要一碳单位来合成核苷酸、进行甲基化反应和维持氧化还原平衡，这些都由一碳代谢提供。一致地，一碳代谢缺陷会导致严重的发育缺陷，如神经管缺陷。然而，这条途径在大脑发育和神经干细胞调节中的作用还知之甚少。为了更好地理解一碳代谢的作用，我们在果蝇大脑发育过程中关注了一碳循环中的关键酶丝氨酸羟甲基转移酶 (Shmt)。我们发现，尽管 Shmt 的缺失不会导致中央脑明显缺陷，但会导致视神经叶严重表型。Shmt 突变体的视神经叶神经上皮较小，部分原因是细胞凋亡增加。此外，shmt 突变体神经上皮存在形态缺陷，无法形成板层沟，这可能解释了观察到的板层神经元缺失。这些发现表明一碳代谢对神经上皮的正常发育至关重要，进而对神经祖细胞和神经元的产生至关重要。这些结果提出了一碳在大脑发育过程中的一种机制作用。
