# Impact of ATF6 deletion on the embryonic brain development

## TL;DR

Deleting ATF6 in developing mouse brains causes microcephaly, neonatal death, and developmental defects, which can be partially reversed with a chemical chaperone.

## Contribution

This study reveals the critical role of ATF6 in embryonic brain development and its coordination of the unfolded protein response.

## Key findings

- Deletion of ATF6α and ATF6β caused microcephaly and neonatal death in mice.
- ATF6 deletion impaired neuronal development, cortical layer formation, and axon projections.
- Administration of 4-phenylbutyric acid partially rescued developmental defects in ATF6-deleted mice.

## Abstract

Although the unfolded protein response (UPR) is activated during brain development, its roles remain unclear. Here, we report that deletion of activating transcription factor 6 (ATF6), consisting of ATF6α and ATF6β, in the developing brain caused microcephaly and neonatal death in mice. Analysis of Atf6a/Atf6b double conditional knockout (dcKO) brains revealed diverse neuronal phenotypes, such as reduced neurogenesis, increased cell death, impaired cortical layer formation, and axon projection defects. Furthermore, hypervasculature, glial defects, and neuroinflammation were observed in dcKO brains. Notably, hypervasculature was detected at E14.5, when endoplasmic reticulum (ER) stress was morphologically unclear, but the UPR was activated to a greater extent in dcKO brains. Expression profiles revealed reduced levels of molecular chaperones in the ER and enhanced levels of PERK- and IRE1-downstream molecules, including VEGFA, in dcKO brains. Administration of a chemical chaperone 4-phenylbutyric acid partially rescued dcKO mice, suggesting roles of ATF6 for improving proteostasis and for coordinating the UPR.

•Deletion of ATF6α and ATF6β caused microcephaly and neonatal death in mice•Deletion of ATF6α and ATF6β impaired neuronal and glial development•A chemical chaperone 4-PBA partially rescued ATF6α- and ATF6β-deleted mice

Deletion of ATF6α and ATF6β caused microcephaly and neonatal death in mice

Deletion of ATF6α and ATF6β impaired neuronal and glial development

A chemical chaperone 4-PBA partially rescued ATF6α- and ATF6β-deleted mice

Neuroscience; Cell biology; Developmental biology