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NF2 is Essential for Human Endoderm Development 

First published: 08 February 2025

Abstract

Vertebrate embryogenesis requires the precisely timed specification of 3 germ cell layers— ectoderm, mesoderm, and endoderm— which give rise to tissues and organs in the developing organism. The tumor suppressor gene NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (Nf2) is expressed in all 3 germ layers during mouse development and its homozygous deletion causes embryonic lethality. People with heterozygous NF2 mutations typically develop Schwann cell tumors, especially vestibular schwannoma, but the specific role of NF2 in human embryonic development is unclear. Here, human induced pluripotent stem cells (hiPSCs) are used to demonstrate that NF2 is essential for endoderm specification and formation in humans. Although endoderm differentiation is not impaired in hiPSCs with heterozygous NF2 mutation, NF2 knockout (NF2−/−) abolished the capacity to form endoderm in vitro, confirmed by loss of expression of endoderm-related genes and proteins, or teratomas in vivo. This defect is mediated by the nuclear translocation of yes-associated protein 1 (YAP1), a transcription co-activator regulating lineage fate via the Hippo pathway and subsequent YAP1-mediated shutdown of Activin/Nodal signaling. Endoderm formation can be rescued via YAP1 knockdown or forced re-expression of NF2 in NF2−/− cells. Taken together, the essential role of NF2 during endoderm specification in human embryogenesis as a regulator of YAP1 is reported.

HoloMonitorinfo

Figure 2 D) Comparison of WT and NF2−/− 1 maximum and average cell thickness using the HoloMonitor. Each dot represents individual cells.

Quantification and Statistical Analysis

In the comparison of cell thickness using a HoloMonitor shown in Figures 2D and 3 different passage numbers of cells were used and at least 3 colonies were measured.

Acknowledgements

The authors would like to thank Dr. Jessica E. Sagers and Nadia A. Atai for performing a literature review that identified exons 2–4 of the NF2 gene as being frequently mutated in patients with NF2-related schwannomatosis, Dr. Shelley Batts for critical review and editing of the manuscript, Dr. Sasa Vasilijic for Holomonitor set up, and Dr. Masaharu Sakagami for assistance with stem cell experiments. The authors sincerely thank the iPS Core Facility at the Harvard Stem Cell Institute for their assistance in generating and characterizing induced pluripotent stem cells. This work was supported by the National Institutes of Health grant R01DC020724, Remondi Foundation, and Bertarelli Foundation Professorship (all K.M.S.).

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