Lush Mark E, Tsai Ya-Yin, Chen Shiyuan, Münch Daniela, Peloggia Julia, Sandler Jeremy E, Piotrowski Tatjana
Stowers Institute for Medical Research, Kansas City, MO, USA.
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
Nat Commun. 2025 Jul 14;16(1):5913. doi: 10.1038/s41467-025-60251-0.
Regeneration and homeostatic turnover of solid tissues depend on the proliferation of symmetrically dividing adult stem cells, which either remain stem cells or differentiate based on their niche position. Here we demonstrate that in zebrafish lateral line sensory organs, stem and progenitor cell proliferation are independently regulated by two cyclinD genes. Loss of ccnd2a impairs stem cell proliferation during development, while loss of ccndx disrupts hair cell progenitor proliferation but allows normal differentiation. Notably, ccnd2a can functionally replace ccndx, indicating that the respective effects of these Cyclins on proliferation are due to cell type-specific expression. However, even though hair cell progenitors differentiate normally in ccndx mutants, they are mispolarized due to hes2 and Emx2 downregulation. Thus, regulated proliferation ensures that equal numbers of hair cells are polarized in opposite directions. Our study reveals cell type-specific roles for cyclinD genes in regulating the different populations of symmetrically dividing cells governing organ development and regeneration, with implications for regenerative medicine and disease.
实体组织的再生和稳态更新依赖于对称分裂的成体干细胞的增殖，这些干细胞要么保持干细胞状态，要么根据其生态位位置进行分化。在这里，我们证明在斑马鱼侧线感觉器官中，干细胞和祖细胞的增殖由两个细胞周期蛋白D基因独立调节。ccnd2a的缺失会损害发育过程中干细胞的增殖，而ccndx的缺失会破坏毛细胞祖细胞的增殖，但允许正常分化。值得注意的是，ccnd2a可以在功能上替代ccndx，这表明这些细胞周期蛋白对增殖的各自影响是由于细胞类型特异性表达。然而，尽管毛细胞祖细胞在ccndx突变体中正常分化，但由于hes2和Emx2的下调，它们的极性发生了错误。因此，受调控的增殖确保了相等数量的毛细胞在相反方向上极化。我们的研究揭示了细胞周期蛋白D基因在调节控制器官发育和再生的对称分裂细胞的不同群体中的细胞类型特异性作用，这对再生医学和疾病具有重要意义。
