Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling

Seiji Ishii; Masaaki Torii; Alexander I Son; Meenu Rajendraprasad; Yury M Morozov; Yuka Imamura Kawasawa; Anna C Salzberg; Mitsuaki Fujimoto; Kristen Brennand; Akira Nakai; Valerie Mezger; Fred H Gage; Pasko Rakic; Kazue Hashimoto-Torii

doi:10.1038/ncomms15157

Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling

Nat Commun. 2017 May 2:8:15157. doi: 10.1038/ncomms15157.

Authors

Seiji Ishii¹, Masaaki Torii^{1

2

3}, Alexander I Son¹, Meenu Rajendraprasad^{1

4}, Yury M Morozov², Yuka Imamura Kawasawa^{5

6

7}, Anna C Salzberg⁷, Mitsuaki Fujimoto⁸, Kristen Brennand^{9

10}, Akira Nakai⁸, Valerie Mezger^{11

12

13}, Fred H Gage¹⁰, Pasko Rakic², Kazue Hashimoto-Torii^{1

2

3}

Affiliations

¹ Center for Neuroscience Research, Children's National Medical Center, Washington, District of Columbia 20010, USA.
² Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
³ Department of Pediatrics, Pharmacology and Physiology, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia 20052, USA.
⁴ Department of Biomedical Engineering, School of Engineering and Applied Science, George Washington University, Washington, District of Columbia 20052, USA.
⁵ Department of Pharmacology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, Pennsylvania 17033, USA.
⁶ Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, Pennsylvania 17033, USA.
⁷ Institute for Personalized Medicine, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, Pennsylvania 17033, USA.
⁸ Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube 755-8505, Japan.
⁹ Department of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
¹⁰ Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA.
¹¹ CNRS, UMR7216 Epigenetics and Cell Fate, Paris 75205, France.
¹² University Paris Diderot, 75205 Paris, France.
¹³ Département Hospitalo-Universitaire DHU PROTECT, Paris 75019, France.

Abstract

Repetitive prenatal exposure to identical or similar doses of harmful agents results in highly variable and unpredictable negative effects on fetal brain development ranging in severity from high to little or none. However, the molecular and cellular basis of this variability is not well understood. This study reports that exposure of mouse and human embryonic brain tissues to equal doses of harmful chemicals, such as ethanol, activates the primary stress response transcription factor heat shock factor 1 (Hsf1) in a highly variable and stochastic manner. While Hsf1 is essential for protecting the embryonic brain from environmental stress, excessive activation impairs critical developmental events such as neuronal migration. Our results suggest that mosaic activation of Hsf1 within the embryonic brain in response to prenatal environmental stress exposure may contribute to the resulting generation of phenotypic variations observed in complex congenital brain disorders.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Brain / drug effects*
Brain / growth & development
Brain / metabolism
Brain / pathology
Cell Movement / drug effects
Embryo, Mammalian
Ethanol / pharmacology
Female
Gene Expression Regulation, Developmental
Heat Shock Transcription Factors / genetics*
Heat Shock Transcription Factors / metabolism
Humans
Hydrogen Peroxide / pharmacology
Injections, Intraperitoneal
Male
Maternal Exposure / adverse effects
Mice
Mice, Transgenic
Neural Stem Cells / cytology
Neural Stem Cells / drug effects*
Neural Stem Cells / metabolism
Neurons / cytology
Neurons / drug effects*
Neurons / metabolism
Phenotype
Pregnancy
Prenatal Exposure Delayed Effects / chemically induced
Prenatal Exposure Delayed Effects / genetics*
Prenatal Exposure Delayed Effects / metabolism
Prenatal Exposure Delayed Effects / pathology
Primary Cell Culture
Signal Transduction

Substances

HSF1 protein, human
Heat Shock Transcription Factors
Hsf1 protein, mouse
Ethanol
Hydrogen Peroxide

Abstract

Publication types

MeSH terms

Substances

Grants and funding