ATF5 deficiency causes abnormal cortical development

Mariko Umemura,Yuji Takahashi,Ryoko Tanabe,Yasuyuki Kaneko

doi:10.1038/s41598-021-86442-5

Mariko Umemura, Yuji Takahashi + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-86442-5

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Abstract

Activating transcription factor 5 (ATF5) is a member of the cAMP response element binding protein (CREB)/ATF family of basic leucine zipper transcription factors. We previously reported that ATF5-deficient (ATF5−/−) mice exhibited behavioural abnormalities, including abnormal social interactions, reduced behavioural flexibility, increased anxiety-like behaviours, and hyperactivity in novel environments. ATF5−/− mice may therefore be a useful animal model for psychiatric disorders. ATF5 is highly expressed in the ventricular zone and subventricular zone during cortical development, but its physiological role in higher-order brain structures remains unknown. To investigate the cause of abnormal behaviours exhibited by ATF5−/− mice, we analysed the embryonic cerebral cortex of ATF5−/− mice. The ATF5−/− embryonic cerebral cortex was slightly thinner and had reduced numbers of radial glial cells and neural progenitor cells, compared to a wild-type cerebral cortex. ATF5 deficiency also affected the basal processes of radial glial cells, which serve as a scaffold for radial migration during cortical development. Further, the radial migration of cortical upper layer neurons was impaired in ATF5−/− mice. These results suggest that ATF5 deficiency affects cortical development and radial migration, which may partly contribute to the observed abnormal behaviours.

Highlights

Activating transcription factor 5 (ATF5) is a member of the cAMP response element binding protein (CREB)/ATF family of basic leucine zipper transcription factors
ATF5 is expressed in the ventricular zone (VZ) and subventricular zone (SVZ), where newly born neurons are generated[7]
The number of phosphorylated histone H3 (PHH3)-positive mitotic cells distal to the VZ was significantly lower in ATF5−/− mice compared to ATF5+/+ mice (Fig. 3g,h), consistent with the reduced intermediate progenitor cells (IPC) numbers in the developing cortex of A TF5−/− mice. These results suggested that the populations of radial glial cells and IPCs were reduced in ATF5−/− mice during cortical development, and ATF5 was sufficient for maintaining the numbers of radial glial cells and IPCs

Summary

Introduction

Activating transcription factor 5 (ATF5) is a member of the cAMP response element binding protein (CREB)/ATF family of basic leucine zipper transcription factors. ATF5 deficiency affected the basal processes of radial glial cells, which serve as a scaffold for radial migration during cortical development. The radial migration of cortical upper layer neurons was impaired in ATF5−/− mice These results suggest that ATF5 deficiency affects cortical development and radial migration, which may partly contribute to the observed abnormal behaviours. ATF5 is highly expressed in neural progenitor cells in the ventricular zone (VZ) and subventricular zone (SVZ) where newly born neurons are g enerated[5,6,7]. ATF5-deficient ( ATF5−/−) mice exhibit behavioural abnormalities, including reduced social interaction and behavioural flexibility, increased anxiety-like behaviours, and hyperactivity in novel e nvironments[8]. Newly born neural progenitors are generated by proliferation of radial glial cells and migrate radially toward the pial surface from the VZ13–16. Defects in radial migration can lead to brain malformations such as lissencephaly and microcephaly, as well as psychiatric disorders such as bipolar disorder, epilepsy, autism spectrum disorder (ASD), and s chizophrenia[12,13,19]

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