LATS1/2 Control Tgfb-Directed Epithelial-to-Mesenchymal Transition in the Murine Dorsal Cranial Neuroepithelium Through Yap Regulation

Authors

Idaliz M Martínez Traverso
Jeffrey D Steimle
Xiaolei Zhao
Jun Wang
James F Martin

Publication Date

9-15-2022

Journal

Development

Abstract

Hippo signaling, an evolutionarily conserved kinase cascade involved in organ size control, plays key roles in various tissue developmental processes, but its role in craniofacial development remains poorly understood. Using the transgenic Wnt1-Cre2 driver, we inactivated the Hippo signaling components Lats1 and Lats2 in the cranial neuroepithelium of mouse embryos and found that the double conditional knockout (DCKO) of Lats1/2 resulted in neural tube and craniofacial defects. Lats1/2 DCKO mutant embryos had microcephaly with delayed and defective neural tube closure. Furthermore, neuroepithelial cell shape and architecture were disrupted within the cranial neural tube in Lats1/2 DCKO mutants. RNA sequencing of embryonic neural tubes revealed increased TGFB signaling in Lats1/2 DCKO mutants. Moreover, markers of epithelial-to-mesenchymal transition (EMT) were upregulated in the cranial neural tube. Inactivation of Hippo signaling downstream effectors, Yap and Taz, suppressed neuroepithelial defects, aberrant EMT and TGFB upregulation in Lats1/2 DCKO embryos, indicating that LATS1/2 function via YAP and TAZ. Our findings reveal important roles for Hippo signaling in modulating TGFB signaling during neural crest EMT.

Keywords

Animals, Cell Cycle Proteins, Epithelial-Mesenchymal Transition, Mice, Protein Serine-Threonine Kinases, Signal Transduction, Skull, Transforming Growth Factor beta, Tumor Suppressor Proteins, Cranial neural crest, Cranial neural tube, Craniofacial development, Hippo signaling, Lats1, Lats2

DOI

10.1242/dev.200860

PMID

36125128

PMCID

PMC9587805

PubMedCentral® Posted Date

9-20-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes