摘要
器官如何感知自身大小并在恰当时机停止生长,是生命科学领域的一个“世纪谜题”.近年来,随着Hippo信号通路的发现与深入研究,这一谜题的面纱正逐渐被揭开.作为不同物种间高度保守的生长调节机制,Hippo信号通路在果蝇和哺乳动物中广泛存在,并在器官尺寸调控中发挥关键作用.该通路以LATS1/2激酶为核心枢纽,整合并传递Hippo或Hippo-like激酶信号,并通过YAP/TAZ转录辅助因子调节下游基因的表达.不同于依赖配体-受体模式的发育信号通路,Hippo通路能够感知物理刺激、结构信号、化学分子以及应激压力等多层次上游信号,而这些信号在发育过程中的具体作用尚待进一步研究.在器官发育、稳态维持和组织再生过程中,Hippo通路不仅通过动态调节细胞增殖与存活来影响细胞数量,还参与指导细胞命运的决定,并在细胞运动与迁移中发挥重要调控作用.因此,靶向Hippo通路以促进组织修复具有广阔的应用前景.本文梳理了Hippo通路研究历程中的重要节点,系统阐述了其分子架构及上游调节机制,探讨了其主要的细胞生物学功能,并以肝脏、心脏和大脑为例,深入分析了该通路在器官发育和再生中的关键作用.同时,本文也对这一领域当前亟待解决的问题和未来的研究方向进行了总结和展望.
How organs perceive their size and know when to stop growing has been an enigma in biology.Recently,the Hippo signaling pathway has emerged as a central growth-control mechanism in development,regeneration,and tumorigenesis,offering crucial insights into this longstanding question.The Hippo pathway was initially identified through genetic mosaic screens in Drosophila for growth-related genes,where mutations in Hippo pathway genes cause striking overgrowth phenotypes of multiple tissues.In mammals,the molecular compositions and biological functions of the Hippo pathway are largely conserved:MST1/2 and MAP4Ks phosphorylate and activate LATS1/2;LATS1/2 in turn phosphorylate and inactivate YAP/TAZ.Several scaffold or adaptor proteins,including WWC1-3,SAV1,MOB1,and NF2,are involved in transducing Hippo signaling.Although the Hippo pathway was initially described as a linear kinase cascade,studies have shown that deletions of genes result in dramatically different phenotypes,which cannot be effectively explained by the traditional model(a linear kinase cascade).Recent studies have reconstructed the Hippo pathway into two signaling modules:MST1/2–SAV1–WWC1-3–LATS1/2(HPO1)and MAP4Ks–NF2–LATS1/2(HPO2).WWC1-3 and NF2 serve as two‘‘loading docks”for LATS1/2 to receive upstream signals from MST1/2 and MAP4Ks,respectively.HPO1 and HPO2 are evolutionarily conserved,exhibit dominant functions in specific cell types,and maintain an antagonistic balance.Unlike many other developmental signaling pathways that depend on specific ligand-receptor mechanisms,the Hippo pathway acts as a signal integrator,sensing and interpreting diverse upstream signals,such as mechanical cues,biochemical molecules,and stress signals.However,the precise molecular mechanisms of how most signals convey information to the Hippo kinases remain largely unknown.Moreover,most upstream signals have been identified in cultured cells.Hence,their in vivo relevance for organ size control needs to be further clarified.Organ growth is a precise and dynamic process coordinated by diverse cellular processes.Beyond modulating proliferation,the Hippo pathway is also vital for orchestrating cell differentiation and migration.During development and regeneration,high YAP/TAZ activity supports cell proliferation and survival,maintains stemness in progenitors,and represses differentiation.YAP/TAZ activity is often unevenly distributed among progenies,driving divergent cell fates:cells with higher YAP/TAZ activity become“helper cells,”while those with lower YAP/TAZ activity become“worker cells.”In addition,the Hippo pathway regulates cell migration,which is also crucial for proper organ development and function.The Hippo pathway has been extensively studied in the liver,heart,and brain.In the liver,YAP/TAZ activity regulates organ size and hepatoblast fate decisions;transient upregulation facilitates regeneration,whereas prolonged activation can lead to fibrosis or tumorigenesis.In the heart,YAP/TAZ supports neonatal cardiomyocyte proliferation and regeneration,a capacity that declines with age.Manipulating Hippo components in adults can boost cardiomyocyte proliferation and facilitate cardiac repair.In the brain,YAP/TAZ promotes neural progenitor cell expansion and astrocyte differentiation,but inappropriate activation impairs neurogenesis.Despite significant advances over the past two decades,several key questions about the Hippo pathway remain unanswered.These include identifying critical upstream signals in organ size control,elucidating cell-type-specific functions in different developmental stages,and developing strategies to modulate YAP/TAZ activity for precise regeneration.In the future,a deeper understanding of the regulatory mechanisms and physiological functions of the Hippo signaling network is critical to leverage its potential for regenerative medicine and cancer treatment.
作者
钟振兴
余发星
Zhenxing Zhong;Fa-Xing Yu(Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China;Children’s Hospital of Fudan University,Fudan University,Shanghai 201102,China)
出处
《科学通报》
北大核心
2025年第15期2205-2220,共16页
Chinese Science Bulletin
基金
国家自然科学基金(32425017,32370770)
国家重点研发计划(2020YFA0803202)
上海市卫生健康委员会(2022XD049)资助。
作者简介
联系人:余发星,E-mail:fxyu@fudan.edu.cn。
