Ras Pathway Proteins
Ras proteins play critical roles in normal physiology and in several disease states. Our laboratory studies these molecules in learning and memory and in cancer.
Figure 1. The diagram presents an overview of signaling via Ras pathway proteins.
Ras-GRF1 Controls the Stress Response Specifically in Adolescent Females
We showed previously that Ras-GRF1 and Ras-GRF2, related calcium-stimulated guanine nucleotide exchange factors (GEFs) that activate both Ras and Rac GTPases, (see Fig. 2) play important but distinct roles in synaptic plasticity in the hippocampus, and learning and memory in post-adolescent male and female mice.
Figure 2. Ras-GRF1 and Ras-GRF2 are related GEFs expressed in hippocampus neurons.
More recently, we have shown that Ras-GRF1 also controls the stress response through two different mechanisms. First, it contributes to the negative feedback role of the hippocampus in controling the Hypothalamus, Pituitary, Adrenal (HPA) axis after short-term stress. Second, after chronic stress Ras-GRF1 begins to contribute to the positive function of the Paraventricular Nucleus (PVN) of the hypothalamus (see Fig. 3) in promoting corticosterone production in response to stress.
Remarkably, both of these Ras-GRF1 functions are displayed in adolescent females, but not in their adolescent male or adult femlae counterparts (see Uzturk et al 2015 ).
Figure 3. Fig. 3. Ras-GRF1 contributes to the HPA axis only in adolescent females through distinct functions in the hippocampus and hypothalamus
At present we are focusing on revealing the genes regulated by Ras-GRF1 that carry out these age and sex-specific functions. Because distorted HPA axis function is thought to contribute to a variety of psychiatric diseases, a full understaning of Ras-GRF1 function in this context may be required to adequetly treat females suffering from stress-associated disorders that begin during adolescence.
Transgeneraltional Inheritance of Anxiety and Defective Social Interactions Induced by Adolescent Exposure to Social Instability
After discovering the transgenerational transmission of the positive effects of an enriched environment (see above), we tested for the transgenerational effects of a negative adolescent experience, social instability. Figure 4 below shows that both elevated anxiety and defective social interactions (preference for social novelty) induced by social instability are passed on to female offspring. Interestingly, even though males do not display these altered behaviors they still pass on these defects to their female offspring (see Saavedra-Rodriguez and Feig 2013 as well as the commentary by Champagne 2013 ). We are presently attempting to detect epigenetic changes in sperm DNA across generations to reveal the molecular mechanisms behind paternal transmission of these effects of the environment on abnormal behavior.
These findings, along with the results from enriched environment experiments, described above add to the growing appreciation that qualities acquired from the environment can be passed on to offspring, a concept first suggested by Lamarck over a century ago. These types of phenomenon may explain some inherited susceptibility to diseases that can not be accounted for by investigating variations in DNA sequence.
Figure 4. Social instability during adolescence increases anxiety and suppresses preference for social novelty (Pref Soc Nov) in future daughters and granddaughters through the paternal lineage and only the former through the maternal lineage.