Matching Items (3)

Filtering by

Clear all filters

134278-Thumbnail Image.png

Dysregulated ERK/MAPK Signaling in RASopathy Animal Model Systems Leads to a Decrease in mTOR Expression and Activation of Translational Machinery

Description

The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development

The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.

Contributors

Agent

Created

Date Created
2017-05

134718-Thumbnail Image.png

Motor Learning Loss Due to MEK1 Hyperactivation in Cortical Excitatory Neurons

Description

Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK

Rasopathies are a family of developmental syndromes that exhibit craniofacial abnormalities, cognitive disabilities, developmental delay and increased risk of cancer. However, little is known about the pathogenesis of developmental defects in the nervous system. Frequently, gain-of-function mutations in the Ras/Raf/MEK/ERK cascade (aka ERK/MAPK) are associated with the observed pathogenesis. My research focuses on defining the relationship between increased ERK/MAPK signaling and its effects on the nervous system, specifically in the context of motor learning. Motor function depends on several neuroanatomically distinct regions, especially the spinal cord, cerebellum, striatum, and cerebral cortex. We tested whether hyperactivation of ERK/MAPK specifically in the cortex was sufficient to drive changes in motor function. We used a series of genetically modified mouse models and cre-lox technology to hyperactivate ERK/MAPK in the cerebral cortex. Nex:Cre/NeuroD6:Cre was employed to express a constitutively active MEK mutation throughout all layers of the cerebral cortex from an early stage of development. RBP4:Cre, caMEK only exhibited hyper activation in cortical glutamatergic neurons responsible for cortical output (neurons in layer V of the cerebral cortex). First, the two mouse strains were tested in an open field paradigm to assess global locomotor abilities and overall fitness for fine motor tasks. Next, a skilled motor reaching task was used to evaluate motor learning capabilities. The results show that Nex:Cre/NeuroD6:Cre, caMEK mutants do not learn the motor reaching task, although they performed normally on the open field task. Preliminary results suggest RBP4:Cre, caMEK mutants exhibit normal locomotor capabilities and a partial lack of learning. The difference in motor learning capabilities might be explained by the extent of altered connectivity in different regions of the corticospinal tract. Once we have identified the neuropathological effects of various layers in the cortex we will be able to determine whether therapeutic interventions are sufficient to reverse these learning defects.

Contributors

Agent

Created

Date Created
2016-12

156111-Thumbnail Image.png

Mechanisms of recovery from chronic stress

Description

Chronic stress results in functional and structural changes to the hippocampus. Decades of research has led to insights into the mechanisms underlying the chronic stress-induced deficits in hippocampal-mediated cognition and reduction of dendritic complexity of hippocampal neurons. Recently, a considerable

Chronic stress results in functional and structural changes to the hippocampus. Decades of research has led to insights into the mechanisms underlying the chronic stress-induced deficits in hippocampal-mediated cognition and reduction of dendritic complexity of hippocampal neurons. Recently, a considerable focus of chronic stress research has investigated the mechanisms behind the improvements in hippocampal mediated cognition when chronic stress ends and a post-stress rest period is given. Consequently, the goal of this dissertation is to uncover the mechanisms that allow for spatial ability to improve in the aftermath of chronic stress. In chapter 2, the protein brain derived neurotrophic factor (BDNF) was investigated as a mechanism that allows for spatial ability to show improvements following the end of chronic stress. It was found that decreasing the expression of BDNF in the hippocampus prevented spatial memory improvements following a post-stress rest period. Chapter 3 was performed to determine whether hippocampal CA3 apical dendritic complexity requires BDNF to show improvements following a post-stress rest period, and whether a receptor for BDNF, TrkB, mediates the improvements of spatial ability and dendritic complexity in a temporal manner, i.e. during the rest period only. These experiments showed that decreased hippocampal BDNF expression prevented improvements in dendritic complexity, and administration of a TrkB antagonist during the rest period also prevented the improvements in spatial ability and dendritic complexity. In chapter 4, the role of the GABAergic system on spatial ability following chronic stress and a post-stress rest period was investigated. Following chronic stress, it was found that male rats showed impairments on the acquisition phase of the RAWM and this correlated with limbic glutamic acid decarboxylase, a marker for GABA. In chapter 5, a transgenic mouse that expresses a permanent marker on all GABAergic interneurons was used to assess the effects of chronic stress and a post-stress rest period on hippocampal GABAergic neurons. While no changes were found on the total number of GABAergic interneurons, specific subtypes of GABAergic interneurons were affected by stressor manipulations. Collectively, these studies reveal some mechanisms behind the plasticity seen in the hippocampus in response to a post-stress rest period.

Contributors

Agent

Created

Date Created
2018