Laboratory of Developmental Genetics, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
Research Bioinformatics, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
EMBO J. 2024 Mar;43(6):956-992. doi: 10.1038/s44318-024-00049-w. Epub 2024 Feb 15.
While most glial cell types in the central nervous system (CNS) arise from neuroectodermal progenitors, some, like microglia, are mesodermally derived. To understand mesodermal glia development and function, we investigated C. elegans GLR glia, which envelop the brain neuropil and separate it from the circulatory system cavity. Transcriptome analysis shows that GLR glia combine astrocytic and endothelial characteristics, which are relegated to separate cell types in vertebrates. Combined fate acquisition is orchestrated by LET-381/FoxF, a fate-specification/maintenance transcription factor also expressed in glia and endothelia of other animals. Among LET-381/FoxF targets, the UNC-30/Pitx2 transcription factor controls GLR glia morphology and represses alternative mesodermal fates. LET-381 and UNC-30 co-expression in naive cells is sufficient for GLR glia gene expression. GLR glia inactivation by ablation or let-381 mutation disrupts locomotory behavior and promotes salt-induced paralysis, suggesting brain-neuropil activity dysregulation. Our studies uncover mechanisms of mesodermal glia development and show that like neuronal differentiation, glia differentiation requires autoregulatory terminal selector genes that define and maintain the glial fate.
虽然中枢神经系统 (CNS) 中的大多数神经胶质细胞类型都起源于神经外胚层祖细胞，但有些细胞，如小胶质细胞，是中胚层衍生的。为了了解中胚层胶质细胞的发育和功能，我们研究了秀丽隐杆线虫的 GLR 胶质细胞，它们包裹着大脑神经胶和将其与循环系统腔隔开。转录组分析表明，GLR 胶质细胞结合了星形胶质细胞和内皮细胞的特征，而在脊椎动物中，这些特征被归为不同的细胞类型。联合命运的获得是由 LET-381/FoxF 协调的，这是一种也在其他动物的胶质细胞和内皮细胞中表达的命运指定/维持转录因子。在 LET-381/FoxF 的靶标中，UNC-30/Pitx2 转录因子控制 GLR 胶质细胞的形态，并抑制替代中胚层命运。在幼稚细胞中共同表达 LET-381 和 UNC-30 足以诱导 GLR 胶质细胞基因的表达。通过消融或 let-381 突变使 GLR 胶质细胞失活会破坏运动行为并促进盐诱导的瘫痪，表明大脑神经胶的活动失调。我们的研究揭示了中胚层胶质细胞发育的机制，并表明与神经元分化一样，胶质细胞分化需要自我调节的终端选择基因，这些基因定义和维持胶质细胞的命运。
