Bosquez Huerta Navish A, Lee Zhung-Fu, Christine Song Eun-Ah, Woo Junsung, Cheng Yi-Ting, Sardar Debosmita, Sert Ozlem, Maleki Ehson, Yu Kwanha, Akdemir Ekin Su, Sanchez Kaitlyn, Jo Juyeon, Rasband Matthew N, Lee Hyun Kyoung, Harmanci Akdes Serin, Deneen Benjamin
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Development, Disease, Models, and Therapeutics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2025 Jan 28;44(1):115121. doi: 10.1016/j.celrep.2024.115121. Epub 2024 Dec 27.
Astrocytes exhibit diverse cellular and molecular properties across the central nervous system (CNS). Recent studies identified region-specific transcription factors (TF) that oversee these diverse properties; how sex differences intersect with region-specific transcriptional programs to regulate astrocyte function is unknown. Here, we show that the TF Nkx6.1 is specifically expressed in ventral astrocytes of the spinal cord and that its deletion results in sex-specific effects on astrocyte morphology. Astrocytes from males exhibit enhanced morphological complexity, accompanied by increased motor function and cholinergic synapses. In contrast, female astrocytes exhibit reduced complexity and no changes in motor function. Mechanistically, we found that Nkx6.1 exhibits sex-specific DNA-binding properties and epigenomic remodeling, identifying Semaphorin 4A (Sema4A) and Gabbr1 as targets regulating astrocyte morphology and cholinergic synapse formation. Collectively, our studies identify astrocytic Nkx6.1 as a key regulator of astrocyte properties in the spinal cord while adding sexual dimorphism as a layer of transcriptional regulation to astrocyte function and circuit activity.
星形胶质细胞在整个中枢神经系统（CNS）中表现出多样的细胞和分子特性。最近的研究确定了负责调控这些多样特性的区域特异性转录因子（TF）；性别差异如何与区域特异性转录程序相互作用以调节星形胶质细胞功能尚不清楚。在此，我们表明转录因子Nkx6.1在脊髓腹侧星形胶质细胞中特异性表达，其缺失会对星形胶质细胞形态产生性别特异性影响。雄性星形胶质细胞表现出增强的形态复杂性，同时运动功能和胆碱能突触增加。相比之下，雌性星形胶质细胞的复杂性降低，运动功能无变化。从机制上讲，我们发现Nkx6.1表现出性别特异性的DNA结合特性和表观基因组重塑，确定信号素4A（Sema4A）和Gabbr1为调节星形胶质细胞形态和胆碱能突触形成的靶点。总体而言，我们的研究确定星形胶质细胞Nkx6.1是脊髓中星形胶质细胞特性的关键调节因子，同时将性别二态性作为星形胶质细胞功能和回路活动转录调控的一个层面。
