Project

Back to overview

Molecular genetic analysis of behavioral defects in mice

English title Molecular genetic analysis of behavioral defects in mice
Applicant Zakany Jozsef
Number 127084
Funding scheme Project funding (Div. I-III)
Research institution Département de Génétique et Evolution Faculté des Sciences Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.12.2009 - 30.11.2012
Approved amount 250'000.00
Show all

Keywords (8)

brain development; sexual behavior; mental illness; molecular pathology; mouse; courtship; behavior; Hox genes

Lay Summary (French)

Lead
Lay summary
The complexity of the human brain and the mind compels researchers to apply animal models with the hope of better understanding mental diseases. Together with many laboratories worldwide we are seeking experimental progress by investigating abnormal mice. In this project we focus on a brain malfunction, which is genetically associated with a genomic locus that codes for transcription factors important for development. This malfunction is represented by abnormal courtship behavior, which is exclusively displayed by females. We aim at understanding the nature of those alterations, in the brain, that underlie this aberrant behavior. We believe that these studies will illuminate the molecular and neural bases of certain instinctive behaviors. In particular our work will help to understand how a specific chromosomal aberration, a micro-deletion, may contribute to mental disorder, and the gender dependence in mental pathologies.La complexité du cerveau humain oblige les chercheurs à utiliser des modèles animaux dans l'espoir d'une meilleure compréhension des maladies mentales. Comme de nombreux laboratoires dans le monde nous prenons une démarche expérimentale en analysant des souris anormales. Dans ce projet nous nous concentrons sur un dysfonctionnement du cerveau, qui est génétiquement associé à certains facteurs de transcription importants pour le développement. Ce dysfonctionnement est représenté par un comportement sexuel anormal, qui est exclusivement mis en œuvres par les femelles. Nous visons à mieux comprendre la nature des modifications, qui sous-tendent ce phénomène dans le cerveau. Nous pensons que ces études révèleront certaines bases moléculaires et neuronales des comportements instinctifs. En particulier, notre travail permettra de comprendre comment une aberration chromosomique spécifique, une courte délétion, peut contribuer à l'apparition de troubles mentaux, et l'influence d'identité sexuelle dans les pathologies mentales.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
A genetic basis for altered sexual behavior in mutant female mice.
Zakany Jozsef, Duboule Denis (2012), A genetic basis for altered sexual behavior in mutant female mice., in Current biology : CB, 22(18), 1676-80.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Structure and Function of Neural Circuits 05.09.2010 Heidelberg Germany


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) A Genetic Basis for Altered sexual Behavior in Mutant Female Mice Institute of Genetics and Evolution, University of Geneva Western Switzerland 02.10.2012
Media relations: print media, online media Behavioural genetics: Genetics of sexual harassment : Research Highlights Nature : Nature Publishing Group International 15.08.2012
Media relations: radio, television Chez les souris, l'amour n'est pas seulement une question d'attirance RTS Le journal- 19:30 Western Switzerland 07.08.2012
Media relations: print media, online media Des souris femelles qui ne pense qu'à ça LE TEMPS, Science & Environnement Western Switzerland 02.10.2012
New media (web, blogs, podcasts, news feeds etc.) Harcèlement et sévices sexuel : Quand la génétique se mêle, Video Vulgariz International 17.08.2012
New media (web, blogs, podcasts, news feeds etc.) Harcèlement et sévices sexuel, Video Section de Biologie, Université de Genève, Western Switzerland 24.09.2012
New media (web, blogs, podcasts, news feeds etc.) Harcèlement et sévices sexuels: quand la génétique s'en mêle Université de Geneve, Service de Communication Western Switzerland 02.08.2012
New media (web, blogs, podcasts, news feeds etc.) Harcèlement sexuel chez la souris (brèves ; 11/10/2012 médecine et sciences International 11.10.2012
Media relations: print media, online media Male Mice Victimized by Females Biology of Reproduction International 08.08.2012
New media (web, blogs, podcasts, news feeds etc.) Quand la génétique se mèle myScience Le Portail Suisse pour la Recherche et Innovation Western Switzerland 02.08.2012

Abstract

BackgroundIn this grant application we focus on mammalian brain malfunctions, which are genetically associated with a locus that codes for transcription factors important for development. We have isolated a novel HoxD cluster mutant mouse line, which shows a highly prevalent aggressive behavior, which is exclusively displayed by females and directed exclusively against males. This grant application aims at understanding the nature of those alterations, in the brain, that underlie this behavior.Working hypothesis Hox genes are usually not functional in higher brain centers. Therefore, we believe that the HoxD-associated disorder in question is caused either by some tightly linked neighbor gene, or by the aberrant regulation of the Hoxd genes themselves, a situation (gain of function) often found in pathological conditions. By studying this mouse mutant strain, we hope to gain new insight into determinants of mental disease. Specific aims and experimental designThe general approach described in this research proposal is to investigate this mouse stock both at the behavioral and molecular level, with the future aim of understanding the physiological alterations responsible for unusual aggressive comportment. We propose to investigate five different, but related questions.1)What are the genomic determinants of this specific behavior defect? We will study a panel of four HoxD cluster alleles, to establish a correlation between the behavioral defect, and the presence or absence of candidate genes and their regulatory regions. We will improve our observation setup to identify mis-behaving individuals. 2)What are the structural changes of the adult brain that correlate with the behavior defect? We will analyze serial histological sections of these brains in order to uncover any gross morphological or cytoarchitectural defects. 3)Which regions of the developing brain express abnormally Hoxd10 transcripts? Preliminary observations indicate ectopic Hoxd10 expression in brain, therefore both males and females of the relevant alleles will be compared in this respect. We will define the brain regions that may be responsible for the behavioral defect by showing aberrant gene expression.4)Are there molecularly detectable consequences in those brain regions that ectopically express Hoxd10 during development? We will analyze marker genes to detect potential alterations, which may be indicative of specific neural circuits. Preliminary observations indicate that midbrain, diencephalic and selected cortical regions should be carefully looked at. Mutant males and females will be compared with respect to both their cellular organization and the status of the main neurotransmitter systems, in those regions known to be involved in aggressive behavior.5)Are there alterations to the expression of other HoxD cluster linked genes? We will analyze the detailed expression patterns of the Evx2, Gad1, Lnp, Mtx2 and Slc25a12 genes, all localized at a close vicinity of the HoxD cluster and thus potential candidate for being de-regulated in the mutant stock.We believe that these studies may help to understand part of the molecular and physiological bases of certain violent behaviors. More specifically, molecular genetic analysis of this mouse mutant will help to understand how a specific chromosomal aberration, a micro-deletion, may contribute to pathological aggression, mood swings and the sex dependence in mental pathologies.
-