He Li, Wen Jiayu, Dai Qi
Department of Molecular Bioscience, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Division of Genome Sciences and Cancer, The John Curtin School of Medical Research, The Australian National University and Australian Research Council Centre of Excellence for the Mathematical Analysis of Cellular Systems, Canberra, Australia.
Elife. 2025 Jul 14;14:RP104076. doi: 10.7554/eLife.104076.
BMP signaling acts as an instructive cue in various developmental processes such as tissue patterning, stem cell proliferation, and differentiation. However, it is not fully understood how this signaling pathway generates different cell-specific outputs. Here, we have identified PRDM16 as a key co-factor for BMP signaling in the mouse brain. PRDM16 contributes to a repressive role of BMP signaling on neural stem cell (NSC) proliferation. We demonstrate that PRDM16 regulates the genomic distribution of BMP pathway transcription factors, the SMAD4/pSMAD complex, preventing the activation of cell proliferation genes. When is lost, the SMAD complex relocates to nearby genomic regions, leading to abnormal upregulation of BMP target genes. This function of PRDM16 is also required for the specification of choroid plexus (ChP) epithelial cells. Through a single-cell resolution fluorescent in situ approach, we have observed that genes co-repressed by SMAD and PRDM16, such as and several cell cycle regulators, become overexpressed in mutant ChP. Our findings elucidate a mechanism through which SMAD4 and pSMAD1/5/8 repress gene expression. Moreover, our study suggests a regulatory circuit composed of BMP and Wnt signaling, along with PRDM16, in controlling stem cell behaviors.
骨形态发生蛋白（BMP）信号在多种发育过程中发挥指导作用，如组织模式形成、干细胞增殖和分化。然而，该信号通路如何产生不同的细胞特异性输出尚不完全清楚。在此，我们确定PRDM16是小鼠大脑中BMP信号的关键辅助因子。PRDM16有助于BMP信号对神经干细胞（NSC）增殖发挥抑制作用。我们证明PRDM16调节BMP信号通路转录因子SMAD4/pSMAD复合物的基因组分布，从而阻止细胞增殖基因的激活。当PRDM16缺失时，SMAD复合物会重新定位到附近的基因组区域，导致BMP靶基因异常上调。脉络丛（ChP）上皮细胞的特化也需要PRDM16的这一功能。通过单细胞分辨率荧光原位方法，我们观察到在PRDM16突变的脉络丛中，与SMAD共同被PRDM16抑制的基因（如某些细胞周期调节因子）过度表达。我们的研究结果阐明了SMAD4和pSMAD1/5/8抑制基因表达的机制。此外，我们的研究提示了一个由BMP和Wnt信号以及PRDM16组成的调控回路，用于控制干细胞行为。
