Role of YAP in early ectodermal specification and a Huntington's Disease model of human neurulation.

TitleRole of YAP in early ectodermal specification and a Huntington's Disease model of human neurulation.
Publication TypeJournal Article
Year of Publication2022
AuthorsPiccolo FM, Kastan NR, Haremaki T, Tian Q, Laundos TL, De Santis R, Beaudoin AJ, Carroll TS, Luo J-D, Gnedeva K, Etoc F, Hudspeth AJ, Brivanlou AH
JournalElife
Volume11
Date Published2022 04 22
ISSN2050-084X
KeywordsCell Cycle Proteins, Ectoderm, Humans, Huntington Disease, Neurogenesis, Neurulation, Signal Transduction, YAP-Signaling Proteins
Abstract

The Hippo pathway, a highly conserved signaling cascade that functions as an integrator of molecular signals and biophysical states, ultimately impinges upon the transcription coactivator Yes-associated protein 1 (YAP). Hippo-YAP signaling has been shown to play key roles both at the early embryonic stages of implantation and gastrulation, and later during neurogenesis. To explore YAP's potential role in neurulation, we used self-organizing neuruloids grown from human embryonic stem cells on micropatterned substrates. We identified YAP activation as a key lineage determinant, first between neuronal ectoderm and nonneuronal ectoderm, and later between epidermis and neural crest, indicating that YAP activity can enhance the effect of BMP4 stimulation and therefore affect ectodermal specification at this developmental stage. Because aberrant Hippo-YAP signaling has been implicated in the pathology of Huntington's Disease (HD), we used isogenic mutant neuruloids to explore the relationship between signaling and the disease. We found that HD neuruloids demonstrate ectopic activation of gene targets of YAP and that pharmacological reduction of YAP's transcriptional activity can partially rescue the HD phenotype.

DOI10.7554/eLife.73075
Alternate JournalElife
PubMed ID35451959
PubMed Central IDPMC9033270
Grant ListR21 DC016984 / DC / NIDCD NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States

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