Dysregulated ERK/MAPK signaling is increasingly implicated as causative in neurodevelopmental syndromes. Cognitive disability can be associated with mutations in canonical components of the RAF/MEK/ERK cascade as well as in upstream modifiers or downstream mediators, and can be associated with either loss or gain of function through the pathway. Collectively, these syndromes are referred to as or """"""""Rasopathies"""""""" or """"""""Ras/MAPK syndromes"""""""". A key impediment to understanding cognitive deficits in Ras/MAPK syndromes is that we know almost nothing about the cell type specific consequences of disrupted ERK/MAPK signaling in the developing brain. A powerful recently emerging concept is that excitatory / inhibitory imbalance underlies the behavioral deficits in many neurodevelopmental disorders. However, the extent to which this concept applies to Ras/MAPK syndromes is unclear. Therefore in Aims 1 and 2 we propose to define the consequences of reduced and enhanced ERK/MAPK signaling for morphological and physiological development of cortical excitatory (Aim 1) versus cortical inhibitory (Aim 2) neurons. A key issue for therapeutics is the potential for reversibility of neurological deficits if ERK/MAPK signaling can be normalized during a critical neurodevelopmental period postnatally. Because ERK can be modified to allow a chemical genetic approach, the ERK/MAPK pathway provides a perfect paradigm to explore reversibility of neurodevelopmental deficits in mouse models. To this end, in Aim 3, we will develop a chemical genetic, cell type specific paradigm for normalizing dysregulated ERK/MAPK signaling in specific classes of cortical neurons.

Public Health Relevance

Recently mutations in genes that code for components of an important intracellular signaling pathway (ERK/MAPK) have been shown to cause neurodevelopmental delay as well as cardiac and craniofacial abnormalities. In order to understand cognitive disability in these syndromes we propose to perturb this ERK/MAPK pathway in specific cell types in the developing brains of experimental animals. In order to develop new strategies for therapeutics we plan to generate an animal model that allows reversal of ERK/MAPK signaling abnormalities in postnatal animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS031768-19
Application #
8302699
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
1993-04-07
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
19
Fiscal Year
2012
Total Cost
$400,803
Indirect Cost
$129,990
Name
University of North Carolina Chapel Hill
Department
Neurology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Xing, Lei; Larsen, Rylan S; Bjorklund, George Reed et al. (2016) Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex. Elife 5:
Xing, Lei; Li, Xiaoyan; Snider, William D (2015) Neurodevelopment. ""RASopathic"" astrocytes constrain neural plasticity. Science 348:636-7
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Xing, Lei; Newbern, Jason M; Snider, William D (2013) Neuronal development: SAD kinases make happy axons. Curr Biol 23:R720-3
Maynard, Thomas M; Gopalakrishna, Deepak; Meechan, Daniel W et al. (2013) 22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development. Hum Mol Genet 22:300-12
Li, Xiaoyan; Newbern, Jason M; Wu, Yaohong et al. (2012) MEK Is a Key Regulator of Gliogenesis in the Developing Brain. Neuron 75:1035-50
Meechan, Daniel W; Tucker, Eric S; Maynard, Thomas M et al. (2012) Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome. Proc Natl Acad Sci U S A 109:18601-6
Meechan, D W; Maynard, T M; Tucker, E S et al. (2011) Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes. Int J Dev Neurosci 29:283-94

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