title: RasGRF1 regulates the hypothalamic-pituitary-adrenal axis specifically in early-adolescent female mice.
abstract: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 min/day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after one, three and five exposures is magnified approximately threefold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females.
authors.affiliation: Sackler School of Graduate Biomedical SciencesDepartments of DevelopmentalMolecular and Chemical BiologyIntegrated Physiology and PathobiologyTufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Belkis Gizem
authors.initials: BG
authors.lastname: Uzturk
authors.affiliation: Sackler School of Graduate Biomedical SciencesDepartments of DevelopmentalMolecular and Chemical BiologyIntegrated Physiology and PathobiologyTufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Shan-Xue
authors.initials: SX
authors.lastname: Jin
authors.affiliation: Sackler School of Graduate Biomedical SciencesDepartments of DevelopmentalMolecular and Chemical BiologyIntegrated Physiology and PathobiologyTufts University School of Medicine, Boston, Massachusetts 02111, USA Sackler School of Graduate Biomedical SciencesDepartments of DevelopmentalMolecular and Chemical BiologyIntegrated Physiology and PathobiologyTufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Beverly
authors.initials: B
authors.lastname: Rubin
authors.affiliation: Sackler School of Graduate Biomedical SciencesDepartments of DevelopmentalMolecular and Chemical BiologyIntegrated Physiology and PathobiologyTufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bartolome
authors.affiliation: Sackler School of Graduate Biomedical SciencesDepartments of DevelopmentalMolecular and Chemical BiologyIntegrated Physiology and PathobiologyTufts University School of Medicine, Boston, Massachusetts 02111, USA Sackler School of Graduate Biomedical SciencesDepartments of DevelopmentalMolecular and Chemical BiologyIntegrated Physiology and PathobiologyTufts University School of Medicine, Boston, Massachusetts 02111, USA larry.feig@tufts.edu.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Feig
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D003345:Corticosterone / Q000097:blood; D005260:Female; D006185:Habituation, Psychophysiologic; D007030:Hypothalamo-Hypophyseal System / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D012149:Restraint, Physical; D012727:Sex Characteristics; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000097:blood / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C513037:Rasgrf1 protein, mouse; D020666:ras-GRF1; D003345:Corticosterone
keywords: HPA axis; RasGRF1; adolescence; female