Fakieh Razan A, Reiner David J
Department of Translational Medical Sciences, School of Medicine, Texas A&M Health Science Center, Texas A&M University, Houston, TX 77030.
Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Imam Abdulrahman bin Faisal University, Dammam 34212, Kingdom of Saudi Arabia.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2414321121. doi: 10.1073/pnas.2414321121. Epub 2024 Dec 31.
Induction of cell fates by growth factors impacts many facets of developmental biology and disease. LIN-3/EGF induces the equipotent vulval precursor cells (VPCs) in to assume the 3˚-3˚-2˚-1˚-2˚-3˚ pattern of cell fates. 1˚ and 2˚ cells become specialized epithelia and undergo stereotyped series of cell divisions to form the vulva. Conversely, 3˚ cells are relatively quiescent and nonspecialized; they divide once and fuse with the surrounding epithelium. 3˚ cells have thus been characterized as passive, uninduced, or ground state. Based on our previous studies, we hypothesized that a 3˚-promoting program would confer resistance to cell fate-transformation by inappropriately activated 1˚ and 2˚ fate-promoting LET-60/Ras and LIN-12/Notch, respectively. Deficient MIG-15/CNH-MAP4 Kinase meets the expectations of genetic interactions for a 3˚-promoting protein. Moreover, endogenous MIG-15 is required for expression of a fluorescent biomarker of 3˚ cell fate, is expressed in VPCs, and functions cell autonomously in VPCs. The Ras family small GTPase RAP-2, orthologs of which activate orthologs of MIG-15 in other systems, emulates these functions of MIG-15. However, gain of RAP-2 function has no effect on patterning, suggesting its activity is constitutive in VPCs. The 3˚ biomarker is expressed independently of the AC, raising questions about the cellular origin of 3˚-promoting activity. Activated LET-60/Ras and LIN-12/Notch repress expression of the 3˚ biomarker, suggesting that the 3˚-promoting program is both antagonized by as well as antagonizes 1˚- and 2˚- promoting programs. This study provides insight into developmental properties of cells historically considered to be nonresponding to growth factor signals.
生长因子诱导细胞命运会影响发育生物学和疾病的许多方面。LIN-3/表皮生长因子（EGF）诱导线虫中的全能性外阴前体细胞（VPCs）呈现3˚-3˚-2˚-1˚-2˚-3˚的细胞命运模式。1˚和2˚细胞分化为特化上皮细胞，并经历一系列模式化的细胞分裂以形成外阴。相反，3˚细胞相对静止且未特化；它们仅分裂一次并与周围上皮细胞融合。因此，3˚细胞被描述为被动、未被诱导或处于基态。基于我们之前的研究，我们推测一个促进3˚细胞命运的程序会赋予细胞对分别由不适当激活的促进1˚和2˚细胞命运的LET-60/Ras和LIN-12/Notch所导致的细胞命运转变的抗性。缺陷型MIG-15/CNH-MAP4激酶符合作为一种促进3˚细胞命运的蛋白质的遗传相互作用预期。此外，内源性MIG-15是3˚细胞命运荧光生物标志物表达所必需的，在VPCs中表达，并在VPCs中发挥细胞自主功能。Ras家族小GTP酶RAP-2在其他系统中其直系同源物可激活MIG-15的直系同源物，它模拟了MIG-15的这些功能。然而，RAP-2功能的增强对模式形成没有影响，这表明其活性在VPCs中是组成型的。3˚生物标志物的表达独立于AC，这引发了关于促进3˚细胞命运活性的细胞起源问题。激活的LET-60/Ras和LIN-12/Notch会抑制3˚生物标志物的表达，这表明促进3˚细胞命运的程序既受到促进1˚和2˚细胞命运的程序的拮抗，同时也拮抗它们。这项研究为历史上被认为对生长因子信号无反应的细胞的发育特性提供了见解。
