Female and Adolescent Specific Roles for RasGRF1 in Regulating the Hypothalamic-Pituitary-Adrenal Axis.
Uzturk, Belkis Gizem.
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 studies on the HPA axis have used adult animals, and among
these the majority has used males. RasGRF... read more1 (GRF1) and RasGRF2 (GRF2) form a family of
calcium-activated guanine nucleotide exchange factors that activates Ras and Rac GTPases
and regulates multiple forms of synaptic plasticity in the CA1 of hippocampus (HC).
Since the HC is known to play a key regulatory role in controlling the HPA axis that
regulates the stress response, we tested the involvement of GRF1 in this process by
comparing the response of GRF1 knockout (GRF1(-/-)) mice and control (WT) mice after
exposure to acute and chronic restraint stress. Here we show that in knockout mice
lacking GRF1, habituation to 30 minutes a day of restraint is markedly accelerated, such
that these mice no longer display elevated corticosterone levels or enhanced locomotion
after 7 days of stress exposure, while WT mice do not even begin to habituate after 14
days of stress. Strikingly, this phenotype is present in early-adolescent female
Ras-GRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female,
or adult female counterparts. Moreover, not only is there a clear response to restraint
stress in early-adolescent female Ras-GRF1 knockout mice after fewer stress exposures,
their response is magnified ~3 fold compared to WT mice. Because animal wide knockout
mice were used in these studies, these complex phenotypes are likely due to a composite
of the effects of GRF1 loss in various brain regions known to regulate the HPA axis. In
fact, we have shown that the loss of GRF1 in the CA1 hippocampus is responsible for the
super-activated HPA axis response observed after short-term stress, which is consistent
with the role of this brain region in HPA axis negative feedback mechanism. Mechanistic
studies have suggested two levels of GRF1 control over the HPA axis response to short
term stress in early-adolescent females; one as a master negative regulator of
phosphorylation changes of proteins in the CA1, and the other as a regulator of gene
expression changes via control over stress-induced alterations in histone H3K9
acetylation. A full understanding of how Ras-GRF1 controls the HPA axis response to
stress may be required to design effective strategies to combat stress-induced
psychiatric disorders initiated in stress-sensitive young
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Biochemistry.
Advisor: Larry Feig.
Committee: Dan Cox, Brian Schaffhausen, Jamie Maguire, and Heather Brenhouse.
Keywords: Biochemistry, and Neurosciences.read less