Redundant type II cadherins define neuroepithelial cell states for cytoarchitectonic robustness

Kou Hiraga,Yasuhiro Go,Yasuhiro Go,Yasuhiro Go,Mayuko Hotta,Takayoshi Inoue,Junko Asami,Mayuko Hotta,Yuki Morimoto,Mikio Hoshino,Yukiko U Inoue,Shoji Tatsumoto

doi:10.1038/s42003-020-01297-2

Abstract

Individual cell shape and integrity must precisely be orchestrated during morphogenesis. Here, we determine function of type II cadherins, Cdh6, Cdh8, and Cdh11, whose expression combinatorially demarcates the mouse neural plate/tube. While CRISPR/Cas9-based single type II cadherin mutants show no obvious phenotype, Cdh6/8 double knockout (DKO) mice develop intermingled forebrain/midbrain compartments as these two cadherins’ expression opposes at the nascent boundary. Cdh6/8/11 triple, Cdh6/8 or Cdh8/11 DKO mice further cause exencephaly just within the cranial region where mutated cadherins’ expression merges. In the Cdh8/11 DKO midbrain, we observe less-constricted apical actin meshwork, ventrally-directed spreading, and occasional hyperproliferation among dorsal neuroepithelial cells as origins for exencephaly. These results provide rigid evidence that, by conferring distinct adhesive codes to each cell, redundant type II cadherins serve essential and shared roles in compartmentalization and neurulation, both of which proceed under the robust control of the number, positioning, constriction, and fluidity of neuroepithelial cells.

Highlights

Individual cell shape and integrity must precisely be orchestrated during morphogenesis
We found no obvious phenotype for single type II Cdh knockout (KO) mice in the developing central nervous system (CNS), Cdh6/8 double knockout (DKO) mice developed intermingled forebrain/midbrain compartments as these two type II Cdhs show mutually exclusive expression at the nascent compartment boundary
In the Cdh8/11 DKO midbrain, we further observed less-constricted apical actin meshwork, ventrally-directed spreading, and occasional hyperproliferation among dorsal neuroepithelial cells as origins toward the exencephalic (EX) phenotype. These results provide the first in vivo evidence that redundant type II Cdhs do confer distinct adhesive codes to each cell to serve essential and shared roles in compartmentalization and neurulation, both of which only proceed under the robust control of the number, positioning, constriction, and fluidity of neuroepithelial cells during early morphogenesis

Summary

Introduction

Individual cell shape and integrity must precisely be orchestrated during morphogenesis. In the Cdh8/11 DKO midbrain, we observe less-constricted apical actin meshwork, ventrally-directed spreading, and occasional hyperproliferation among dorsal neuroepithelial cells as origins for exencephaly These results provide rigid evidence that, by conferring distinct adhesive codes to each cell, redundant type II cadherins serve essential and shared roles in compartmentalization and neurulation, both of which proceed under the robust control of the number, positioning, constriction, and fluidity of neuroepithelial cells. Loss of function studies using mouse indicated that, in striking contrast with the early embryonic lethal phenotype for type I Cdh[1] (=E-cadherin)-/-34 or Cdh[2] (=Ncadherin)-/-35 mice, most type II Cdh single knockout mice and some combinatorial mutants show few embryonic phenotypes despite the considerable levels of early expression[31,36,37,38,39]. This has often been ascribed to “molecular and/or functional redundancy”

Methods

Results

Conclusion