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.
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.
|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|
|Newbern, Jason M; Li, Xiaoyan; Shoemaker, Sarah E et al. (2011) Specific functions for ERK/MAPK signaling during PNS development. Neuron 69:91-105|
|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|
|Tucker, Eric S; Lehtinen, Maria K; Maynard, Tom et al. (2010) Proliferative and transcriptional identity of distinct classes of neural precursors in the mammalian olfactory epithelium. Development 137:2471-81|
|Rawson, N E; Lischka, F W; Yee, K K et al. (2010) Specific mesenchymal/epithelial induction of olfactory receptor, vomeronasal, and gonadotropin-releasing hormone (GnRH) neurons. Dev Dyn 239:1723-38|
|Meechan, Daniel W; Tucker, Eric S; Maynard, Thomas M et al. (2009) Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. Proc Natl Acad Sci U S A 106:16434-45|
|Tucker, Eric S; Segall, Samantha; Gopalakrishna, Deepak et al. (2008) Molecular specification and patterning of progenitor cells in the lateral and medial ganglionic eminences. J Neurosci 28:9504-18|
|Newbern, Jason; Zhong, Jian; Wickramasinghe, Rasika S et al. (2008) Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc Natl Acad Sci U S A 105:17115-20|
|Willard, Melinda D; Willard, Francis S; Li, Xiaoyan et al. (2007) Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation. EMBO J 26:2029-40|
|Meechan, D W; Maynard, T M; Wu, Y et al. (2006) Gene dosage in the developing and adult brain in a mouse model of 22q11 deletion syndrome. Mol Cell Neurosci 33:412-28|
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