Department of Genetics and Biotechnology, College of Life Sciences, Graduate School of Biotechnology, Kyung Hee University, Yongin, Gyeonggi, Republic of Korea.
Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin, Gyeonggi, Republic of Korea.
Cell Death Differ. 2023 Jun;30(6):1563-1574. doi: 10.1038/s41418-023-01165-6. Epub 2023 Apr 20.
At the top of the midbrain is the inferior colliculus (IC), which functions as the major hub for processing auditory information. Despite the functional significance of neurons in the IC, our understanding of their formation is limited. In this study, we identify the embryonic patterning gene Dbx1 as a key molecular player that governs genetic programs for IC survival. We find that Dbx1 plays a critical role in preventing apoptotic cell death in postnatal IC by transcriptionally repressing c-Jun and pro-apoptotic BH3 only factors. Furthermore, by employing combined approaches, we uncover that Tcf7l2 functions downstream of Dbx1. Loss of Tcf7l2 function causes IC phenotypes with striking similarity to those of Dbx1 mutant mice, which include defective embryonic maturation and postnatal deletion of the IC. Finally, we demonstrate that the Dbx1-Tcf7l2 cascade functions upstream of Ap-2δ, which is essential for IC development and survival. Together, these results unravel a novel molecular mechanism for IC maintenance, which is indispensable for normal brain development.
中脑的顶部是下丘（IC），它是处理听觉信息的主要枢纽。尽管 IC 中的神经元具有重要的功能，但我们对其形成的理解还很有限。在这项研究中，我们确定了胚胎模式基因 Dbx1 是一个关键的分子调控因子，它控制着 IC 存活的遗传程序。我们发现 Dbx1 通过转录抑制 c-Jun 和促凋亡 BH3 仅因子，在出生后 IC 中发挥关键作用，防止细胞凋亡。此外，通过采用联合方法，我们揭示了 Tcf7l2 是 Dbx1 的下游作用因子。Tcf7l2 功能丧失会导致 IC 表型与 Dbx1 突变小鼠非常相似，包括胚胎成熟缺陷和出生后 IC 删除。最后，我们证明了 Dbx1-Tcf7l2 级联作用于 Ap-2δ 的上游，Ap-2δ 对于 IC 的发育和存活是必不可少的。总之，这些结果揭示了 IC 维持的一种新的分子机制，对于正常的大脑发育是不可或缺的。
