Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden.
Development. 2022 Nov 15;149(22). doi: 10.1242/dev.201262. Epub 2022 Nov 16.
The regulatory circuits that coordinate epidermal differentiation during development are still not fully understood. Here, we report that the transcriptional regulator ID1 is enriched in mouse basal epidermal progenitor cells and find ID1 expression to be diminished upon differentiation. In utero silencing of Id1 impairs progenitor cell proliferation, leads to precocious delamination of targeted progenitor cells and enables differentiated keratinocytes to retain progenitor markers and characteristics. Transcriptional profiling suggests that ID1 acts by mediating adhesion to the basement membrane while inhibiting spinous layer differentiation. Co-immunoprecipitation reveals ID1 binding to transcriptional regulators of the class I bHLH family. We localize bHLH Tcf3, Tcf4 and Tcf12 to epidermal progenitor cells during epidermal stratification and establish TCF3 as a downstream effector of ID1-mediated epidermal proliferation. Finally, we identify crosstalk between CEBPA, a known mediator of epidermal differentiation, and Id1, and demonstrate that CEBPA antagonizes BMP-induced activation of Id1. Our work establishes ID1 as a key coordinator of epidermal development, acting to balance progenitor proliferation with differentiation and unveils how functional crosstalk between CEBPA and Id1 orchestrates epidermal lineage progression.
发育过程中协调表皮分化的调控回路尚不完全清楚。在这里，我们报告转录调节因子 ID1 在小鼠基底表皮祖细胞中富集，并发现 ID1 的表达在分化时减少。在体内沉默 Id1 会损害祖细胞的增殖，导致靶向祖细胞过早分层，并使分化的角质形成细胞保留祖细胞标记和特征。转录谱分析表明，ID1 通过介导与基底膜的黏附而抑制棘层分化来发挥作用。共免疫沉淀显示 ID1 与 I 类 bHLH 家族的转录调节因子结合。我们在表皮分层过程中将 bHLH Tcf3、Tcf4 和 Tcf12 定位到表皮祖细胞中，并确定 TCF3 是 ID1 介导的表皮增殖的下游效应子。最后，我们鉴定了已知介导表皮分化的 CEBPA 与 Id1 之间的串扰，并证明 CEBPA 拮抗 BMP 诱导的 Id1 激活。我们的工作确立了 ID1 作为表皮发育的关键协调因子，其作用是平衡祖细胞增殖与分化，并揭示了 CEBPA 和 Id1 之间的功能串扰如何协调表皮谱系进展。
