Lin Chi-Iou, Merley Anne, Wada Hiromi, Zheng Jianwei, Jaminet Shou-Ching S
Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Anesthesiology Department, Riverview Hospital, Noblesville, IN 46060, USA.
Curr Issues Mol Biol. 2024 Nov 18;46(11):13105-13118. doi: 10.3390/cimb46110781.
Transmembrane-4 L-six family member-1 (TM4SF1) is a small cell surface glycoprotein that is highly and selectively expressed on endothelial cell and mesenchymal stem cell surfaces. TM4SF1 regulates cellular functions by forming protein complexes called TMED (TM4SF1-enriched microdomains) that either recruit growth-factor activated proteins and internalize them via microtubules to distribute the recruited molecules intracellularly or support the formation of nanopodia for intercellular interactions extracellularly. Through a genetically manipulated mouse model for global gene knockout, we demonstrate here that TM4SF1 is essential for blood vessel development. -null embryos fail to develop blood vessels and experience lethality at E9.5. -heterozygous embryos are smaller in body size during early embryonic development, and almost half die in utero due to intracranial hemorrhage in the intraventricular and subarachnoid space, which becomes apparent by E17.5. Surviving -heterozygotes do not display overt phenotypic differences relative to wild type littermates postnatally. Together, these studies demonstrate that TM4SF1, through its molecular facilitator and nanopodia formation roles in TMED, intimately regulates blood vessel formation during embryonic development.
跨膜4 L-六家族成员1（TM4SF1）是一种小的细胞表面糖蛋白，在内皮细胞和间充质干细胞表面高度且选择性表达。TM4SF1通过形成称为TMED（富含TM4SF1的微结构域）的蛋白质复合物来调节细胞功能，该复合物要么招募生长因子激活蛋白并通过微管将其内化，以便在细胞内分布所招募的分子，要么支持在细胞外形成纳米伪足以进行细胞间相互作用。通过一种用于全局基因敲除的基因操作小鼠模型，我们在此证明TM4SF1对血管发育至关重要。基因敲除的胚胎无法发育血管，并在胚胎第9.5天死亡。基因敲除杂合子胚胎在早期胚胎发育期间体型较小，并且几乎一半在子宫内死亡，原因是脑室内和蛛网膜下腔的颅内出血，这种情况在胚胎第17.5天变得明显。存活的基因敲除杂合子在出生后相对于野生型同窝仔没有表现出明显的表型差异。总之，这些研究表明，TM4SF1通过其在TMED中的分子促进和纳米伪足形成作用，密切调节胚胎发育过程中的血管形成。
