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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00337

Sex hormones regulate SHANK gene expression

 Simone Berkel1*,  Ahmed Eltokhi1, 2, Henning Froehlich1, Diana Porras Gonzalez1,  Rafiullah Rafiullah1,  Rolf Sprengel2 and  Gudrun A. Rappold1
  • 1Institute of Human Genetics, University Hospital Heidelberg, Germany
  • 2Institut für Anatomie und Zellbiologie, Universität Heidelberg, Germany

Autism spectrum disorders (ASD) have a higher prevalence in male individuals compared to females, with a ratio of affected boys compared to girls of 4 : 1 for ASD and 11 : 1 for Asperger syndrome. Mutations in the SHANK genes (comprising SHANK1, SHANK2 and SHANK3), coding for postsynaptic scaffolding proteins, have been tightly associated with ASD. As early brain development is strongly influenced by sex hormones, we investigated the effect of dihydrotestosterone and 17β-estradiol on SHANK expression in a human neuroblastoma cell model. Both sex hormones had a significant impact on the expression of all three SHANK genes, which could be effectively blocked by androgen and estrogen receptor antagonists. In neuron-specific androgen receptor knock-out mice (ArNesCre), we found a nominal significant reduction of all Shank genes at postnatal day 7.5 in the cortex. In the developing cortex of wild-type CD1 mice, a sex-differential protein expression was identified for all Shanks at embryonic day 17.5 and postnatal day 7.5 with significantly higher protein levels in male compared to female pubs. Together, we could show that SHANK expression is influenced by sex hormones leading to a sex-differential expression, thus providing novel insights into the sex bias in ASD.

Keywords: Autism spectrum disorders (ASD), sex differences, shank, SH-SY5Y cells, Dihydrotestosterone, 17ß-Estradiol, androgen receptor knock-out mouse

Received: 30 Apr 2018; Accepted: 28 Aug 2018.

Edited by:

Eunjoon Kim, Institute for Basic Science (IBS), South Korea

Reviewed by:

Andreas M. Grabrucker, University of Limerick, Ireland
Yong-Seok Lee, Seoul National University College of Medicine, South Korea  

Copyright: © 2018 Berkel, Eltokhi, Froehlich, Porras Gonzalez, Rafiullah, Sprengel and Rappold. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Simone Berkel, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany,