Kilpinen Sami, Virtanen Lassi, Bodington Celma Silvana, Bonsdorff Amos, Heliölä Heidi, Achim Kaia, Partanen Juha
Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Elife. 2025 Sep 12;14:RP105867. doi: 10.7554/eLife.105867.
Selector transcription factors (TFs) control choices of alternative cellular fates during development. The ventral rhombomere 1 of the embryonic mouse () brainstem produces neuronal precursors that can differentiate into either inhibitory GABAergic or excitatory glutamatergic neurons important for the control of behaviour. TFs , , and are required for adopting the GABAergic neuronal identity and inhibiting the glutamatergic identity. Here, we asked how these selector TFs are activated and how they control the identity of the developing brainstem neurons. We addressed these questions by analysing chromatin accessibility at putative gene regulatory elements active during GABAergic and glutamatergic neuron lineage bifurcation, combined with studies of TF expression and DNA binding. Our results show that the , , and genes are activated by highly similar mechanisms, with connections to regional patterning, neurogenic cell cycle exit and general course of neuronal differentiation. After activation, , , and are linked by auto- and cross-regulation as well as regulatory interactions with TFs of the glutamatergic branch. Predicted targets of these selector TFs include genes expressed in GABAergic neurons, glutamatergic neurons, or both. Unlike genes specific to the glutamatergic branch, the genes expressed in GABAergic neurons appear to be under combinatorial control of , , and . Understanding gene regulatory interactions affecting the anterior brainstem GABAergic and glutamatergic neuron differentiation may give genetic and mechanistic insights into neurodevelopmental traits and disorders.
选择转录因子（TFs）在发育过程中控制细胞命运的选择。胚胎小鼠脑干的腹侧菱脑节1产生神经元前体，这些前体可分化为抑制性GABA能神经元或兴奋性谷氨酸能神经元，这对于行为控制很重要。采用GABA能神经元身份并抑制谷氨酸能身份需要TFs 、 和 。在这里，我们研究了这些选择转录因子是如何被激活的，以及它们如何控制发育中脑干神经元的身份。我们通过分析在GABA能和谷氨酸能神经元谱系分叉期间活跃的假定基因调控元件处的染色质可及性，并结合TF表达和DNA结合的研究来解决这些问题。我们的结果表明， 、 和 基因通过高度相似的机制被激活，与区域模式形成、神经源性细胞周期退出和神经元分化的一般过程有关。激活后， 、 和 通过自我调节和交叉调节以及与谷氨酸能分支的TFs的调控相互作用而联系在一起。这些选择转录因子的预测靶点包括在GABA能神经元、谷氨酸能神经元或两者中表达的基因。与谷氨酸能分支特有的基因不同，在GABA能神经元中表达的基因似乎受到 、 和 的组合控制。了解影响前脑干GABA能和谷氨酸能神经元分化的基因调控相互作用，可能会为神经发育特征和疾病提供遗传学和机制方面的见解。
