Lima1 mediates the pluripotency control of membrane dynamics and cellular metabolism

Binyamin Duethorn,Magdalena Zernicka-Goetz,Marc P Stemmler,Dagmar Zeuschner,Karina Mildner,Hannes C A Drexler,Fabian Groll,Martin Stehling,Heike Brinkmann,Ludmila Kremer,Ivan Bedzhov,Bettina Rieger,Marie-Theres Borowski,Karin B Busch,Juan M Vaquerizas

doi:10.1038/s41467-022-28139-5

Abstract

Lima1 is an extensively studied prognostic marker of malignancy and is also considered to be a tumour suppressor, but its role in a developmental context of non-transformed cells is poorly understood. Here, we characterise the expression pattern and examined the function of Lima1 in mouse embryos and pluripotent stem cell lines. We identify that Lima1 expression is controlled by the naïve pluripotency circuit and is required for the suppression of membrane blebbing, as well as for proper mitochondrial energetics in embryonic stem cells. Moreover, forcing Lima1 expression enables primed mouse and human pluripotent stem cells to be incorporated into murine pre-implantation embryos. Thus, Lima1 is a key effector molecule that mediates the pluripotency control of membrane dynamics and cellular metabolism.

Highlights

Lima[1] is an extensively studied prognostic marker of malignancy and is considered to be a tumour suppressor, but its role in a developmental context of non-transformed cells is poorly understood
We examined the localisation of the major components of the cadherin-catenin complex (CCC), namely E-cad, α-E-catenin (α-E-cat), N-cadherin (N-cad), α-N-catenin (α-N-cat) and β-cat
Using available transcriptomics data[20], we found that Lima[1] mRNA is present in GV and MII oocytes as maternal transcripts, and later the zygotic expression exhibits a sharp increase after the 16-cell stage (Fig. 1b)

Summary

Introduction

Lima[1] is an extensively studied prognostic marker of malignancy and is considered to be a tumour suppressor, but its role in a developmental context of non-transformed cells is poorly understood. We characterise the expression pattern and examined the function of Lima[1] in mouse embryos and pluripotent stem cell lines. Forcing Lima[1] expression enables primed mouse and human pluripotent stem cells to be incorporated into murine pre-implantation embryos. The cancer cells often reprogramme their energy metabolism, lose epithelial morphology and activate invasion and metastasis, enabling a benign adenoma to transform into an invasive carcinoma, which correlates with poor patient prognosis. The process of EMT as well as the activation of several signalling pathways, such as Wnt, Notch and Hedgehog, are common features in both embryonic development and cancer[3]. The. EMT, which mediates E-cadherin (E-cad) downregulation, is the driving force enabling malignancy and is a key step in the process of gastrulation[1]. Aberrant activation of this pathway can initiate tumorigenesis by promoting the expression of downstream oncogenes[6]

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Conclusion