TY - JOUR
T1 - Paternal aging affects behavior in Pax6 mutant mice
T2 - A gene/environment interaction in understanding neurodevelopmental disorders
AU - Yoshizaki, Kaichi
AU - Furuse, Tamio
AU - Kimura, Ryuichi
AU - Tucci, Valter
AU - Kaneda, Hideki
AU - Wakana, Shigeharu
AU - Osumi, Noriko
N1 - Funding Information:
The authors thank the Japan Mouse Clinic at RIKEN Biological Resource Center, Dr. Ikuko Yamada, Ms. Tomoko Kushida and Ms. Kashimura Misho for production of mice via IVF and their maintenance, Dr. Yosefu Arime for scientific discussion, and Ms. Sayaka Makino for animal care. The authors are also grateful to all members of their laboratory for fruitful discussions. This work was supported in part by KAKENHI (25640002 to K.Y. and 16H06530 to N.O.) from Ministry of Education, Culture, Sports, Science and Technology of Japan.
Publisher Copyright:
© 2016 Yoshizaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/11
Y1 - 2016/11
N2 - Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes) born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT) mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies.
AB - Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes) born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT) mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies.
UR - http://www.scopus.com/inward/record.url?scp=84995698705&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84995698705&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0166665
DO - 10.1371/journal.pone.0166665
M3 - Article
C2 - 27855195
AN - SCOPUS:84995698705
SN - 1932-6203
VL - 11
JO - PLoS ONE
JF - PLoS ONE
IS - 11
M1 - e0166665
ER -