2. Academic Validation
  3. NF2 is Essential for Human Endoderm Development

NF2 is Essential for Human Endoderm Development

  • Adv Sci (Weinh). 2025 May;12(17):e2410909. doi: 10.1002/advs.202410909.
Minjin Jeong 1 2,  Dongjun Han 1 2,  Preetida Bhetariya 3,  D Bradley Welling 2,  Miodrag Stojkovic 2,  Konstantina M Stankovic 1 2 4 5
Affiliations

Affiliations

  • 1 Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 2 Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, MA, 02114, USA.
  • 3 Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
  • 4 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94304, USA.
  • 5 Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, 94305, USA.
PMID: 39921490 DOI: 10.1002/advs.202410909
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.

Keywords

NF2; YAP1; endoderm; hippo pathway; human induced pluripotent stem cells.

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