Open AccessOscillatory expression of Hes1 regulates cell proliferation and neuronal differentiation in the embryonic brain
Author(s) -
Shohei Ochi,
Yui Imaizumi,
Hiromi Shimojo,
Hitoshi Miyachi,
Ryoichiro Kageyama
Publication year - 2020
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.182204
Subject(s) - hes1 , biology , neurogenesis , microbiology and biotechnology , mutant , embryonic stem cell , wild type , neural stem cell , cellular differentiation , genetics , notch signaling pathway , gene , stem cell , signal transduction
The expression of the transcriptional repressor Hes1 oscillates in many cell types, including neural progenitor cells (NPCs), but the significance of Hes1 oscillations in development is not fully understood. To examine the effect of altered oscillatory dynamics of Hes1, we generated two types of Hes1 knock-in mice, a shortened (type-1) and an elongated (type-2) Hes1 gene, and examined their phenotypes focusing on neural development. While both mutations affected Hes1 oscillations, the type-1 mutation dampened Hes1 oscillations more severely, resulting in much lower amplitudes. The average levels of Hes1 expression in type-1-mutant NPCs were also lower than in wild-type NPCs but similar to or slightly higher than those in Hes1 heterozygous mutant mice, which exhibit no apparent defects. While type-2-mutant mice were apparently normal, type-1-mutant mice displayed smaller brains than wild-type mice and up-regulated proneural gene expression. Furthermore, proliferation of NPCs decreased and cell death increased in type-1-mutant embryos. When Hes3 and Hes5 were additionally deleted, neuronal differentiation was also accelerated, leading to microcephaly. Thus, robust Hes1 oscillations are required for maintenance and proliferation of NPCs and the normal timing of neurogenesis, thereby regulating brain morphogenesis.