Dataset Information

Stk40 deletion elevates c-JUN protein level and impairs mesoderm differentiation.

ABSTRACT: Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) toward the extraembryonic endoderm, and Stk40 knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological functions of STK40 in mesoderm differentiation remain elusive. Here, we report that Stk40 ablation impairs mesoderm differentiation both in vitro and in vivo Mechanistically, STK40 interacts with both the E3 ubiquitin ligase mammalian constitutive photomorphogenesis protein 1 (COP1) and the transcriptional regulator proto-oncogene c-Jun (c-JUN), promoting c-JUN protein degradation. Consequently, Stk40 knockout leads to c-JUN protein accumulation, which, in turn, apparently suppresses WNT signaling activity and impairs the mesoderm differentiation process. Overall, this study reveals that STK40, together with COP1, represents a previously unknown regulatory axis that modulates the c-JUN protein level within an appropriate range during mesoderm differentiation from mESCs. Our findings provide critical insights into the molecular mechanisms regulating the c-JUN protein level and may have potential implications for managing cellular disorders arising from c-JUN dysfunction.

SUBMITTER: Hu J

PROVIDER: S-EPMC6597834 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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<i>Stk40</i> deletion elevates c-JUN protein level and impairs mesoderm differentiation.

Hu Jing J Li Shuang S Sun Xiaozhi X Fang Zhuoqing Z Wang Lina L Xiao Feng F Shao Min M Ge Laixiang L Tang Fan F Gu Junjie J Yu Hongyao H Guo Yueshuai Y Guo Xuejiang X Liao Bing B Jin Ying Y

The Journal of biological chemistry 20190515 25

Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) toward the extraembryonic endoderm, and <i>Stk40</i> knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological fu ...[more]

PMID: 31092598

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Project description:The Dishevelled proteins transduce both canonical Wnt/β-catenin and non-canonical Wnt/planar cell polarity (PCP) signaling pathways to regulate many key developmental processes during embryogenesis. Here, we disrupt both canonical and non-canonical Wnt pathways by targeting the entire Dishevelled family of genes (Dvl1, Dvl2, and Dvl3) to investigate their functional roles in the early embryo. We identified several defects in anterior-posterior axis specification and mesoderm patterning in Dvl1+/-; Dvl2-/-; Dvl3-/- embryos. Homozygous deletions in all three Dvl genes (Dvl TKO) resulted in defects in distal visceral endoderm migration and a complete failure to induce mesoderm formation. To identify potential mechanisms that lead to the defects in the developmental processes preceding gastrulation, we generated Dvl TKO mouse embryonic stem cells (mESCs) and compared the transcriptional profile of these cells with wild-type (WT) mESCs during germ lineage differentiation into 3D embryoid bodies (EBs). While the Dvl TKO mESCs displayed similar morphology, self-renewal properties, and minor transcriptional variation from WT mESCs, we identified major transcriptional dysregulation in the Dvl TKO EBs during differentiation in a number of genes involved in anterior-posterior pattern specification, gastrulation induction, mesenchyme morphogenesis, and mesoderm-derived tissue development. The absence of the Dvls leads to specific down-regulation of BMP signaling genes. Furthermore, exogenous activation of canonical Wnt, BMP, and Nodal signaling all fail to rescue the mesodermal defects in the Dvl TKO EBs. Moreover, endoderm differentiation was promoted in the absence of mesoderm in the Dvl TKO EBs, while the suppression of ectoderm differentiation was delayed. Overall, we demonstrate that the Dvls are dispensable for maintaining self-renewal in mESCs but are critical during differentiation to regulate key developmental signaling pathways to promote proper axis specification and mesoderm formation.

Dataset Information

Stk40 deletion elevates c-JUN protein level and impairs mesoderm differentiation.

Publications

<i>Stk40</i> deletion elevates c-JUN protein level and impairs mesoderm differentiation.

Similar Datasets

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