Tsiarli Maria A, Kentro James A, Conard Ashley M, Xu Lucy, Nguyen Erica, O'Connor-Giles Kate, Larschan Erica N
Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA Department 02115, USA.
bioRxiv. 2025 Jul 7:2020.10.09.333831. doi: 10.1101/2020.10.09.333831.
Neural stem cell (NSC) differentiation is controlled by cell-intrinsic and external signals from the stem cell niche including niche surface glia (SG). However, the mechanisms by which transcription factors drive NSC differentiation within the niche remain largely unknown. Here, we show that the melanogaster transcription factor, Chromatin-linked adaptor for MSL proteins (CLAMP) is required for regulation of stemness and proliferation of NSCs, especially of the optic lobe (OL). CLAMP promotes transcription of genes involved in stemness, proliferation, and glial development and represses transcription of genes involved in neurogenesis and niche survival. Consistent with transcriptional changes, CLAMP promotes NSC proliferation and niche SG production, while lack of CLAMP severely and specifically impacts OL development. To identify potential mechanisms by which CLAMP may regulate brain development, we examined CLAMP motifs and available CLAMP ChIP-seq data to determine which genes may be direct versus indirect targets. CLAMP motifs are present at many target genes including the glial-determining gene, while , the master regulator of OL-development is directly bound by CLAMP. In accordance to these results, in larval OL NSCs lacking CLAMP, Tailless levels are decreased dramatically, suggesting that CLAMP controls OL neurogenesis Tailless. Overall, our results suggest that CLAMP regulates a transcriptional program which drives NSC proliferation and differentiation cell-intrinsic and niche-dependent mechanisms that involve transcriptional regulation of and niche glia.
神经干细胞（NSC）的分化受细胞内在信号以及来自干细胞微环境的外部信号控制，这些外部信号包括微环境表面神经胶质细胞（SG）。然而，转录因子在微环境中驱动NSC分化的机制仍 largely未知。在这里，我们表明果蝇转录因子，MSL蛋白的染色质连接衔接子（CLAMP）是NSC干性和增殖调控所必需的，尤其是对视叶（OL）的调控。CLAMP促进参与干性、增殖和神经胶质发育的基因转录，并抑制参与神经发生和微环境存活的基因转录。与转录变化一致，CLAMP促进NSC增殖和微环境SG产生，而缺乏CLAMP则严重且特异性地影响OL发育。为了确定CLAMP可能调控大脑发育的潜在机制，我们检查了CLAMP基序和可用的CLAMP ChIP-seq数据，以确定哪些基因可能是直接或间接靶点。CLAMP基序存在于许多靶基因中，包括神经胶质决定基因，而OL发育的主调控因子直接与CLAMP结合。根据这些结果，在缺乏CLAMP的幼虫OL NSCs中，无尾水平显著降低，这表明CLAMP通过无尾控制OL神经发生。总体而言，我们的结果表明，CLAMP调控一个转录程序，该程序通过涉及 和微环境神经胶质转录调控的细胞内在和微环境依赖性机制驱动NSC增殖和分化。
