22q11Deletion Syndrome (22q11DS, also known as DiGeorge or Velocardiofacial Syndrome) occurs in approximately 1/3000 live births and confers increased vulnerability for language and social cognition deficits, attention deficit/hyperactivity disorder, autism, mood disorders, and schizophrenia. There is general consensus that these disorders reflect compromised development or maintenance of cortical neurons and circuits;nevertheless, cellular and molecular pathogenic mechanisms remain ill defined. The association of behavioral disorders of cortical circuitry with a specific genetic lesion-deletion of 1.5 to 3.0MB at hChr.22, position q11-provides an opportunity to evaluate cellular and molecular mechanisms that contribute to pathogenesis. In the first phase of this project we found that a large set of genes deleted in 22q11DS are expressed at specific times in distinct regions and cell classes in the developing and adult nervous system. Our functional analysis of mouse 22q11 orthologues divides these genes into 3 categories: 1.) Genes regulated by signaling molecules that influence induction and morphogenesis at 22q11DS phenotypic sites including the heart, face, thymus, limbs, and forebrain. 2.) Genes implicated in cell cycle regulation. 3.) Genes localized to mitochondria that influence cellular metabolism. The expression dynamics and patterns, as well as apparent functions of each gene subset, suggests a new hypothesis of how 22q11 deletion alters cortical circuit development: altered dosage of functionally distinct 22q11 gene subsets disrupts specification, proliferation, migration, growth and circuit differentiation of cortical neurons or their precursors. To test this hypothesis, we will pursue 3 Specific Aims. 1.) We will assess interaction between diminished 22q11 gene dosage and inductive signaling that influences cortical regional identity and neurogenic capacity. We focus on reciprocal regulation of 22q11 genes, sonic hedgehog, retinoic acid, and bone morphogenetic signaling pathways. 2.) We will define consequences of diminished 22q11 gene dosage for cortical neurogenesis and migration. We assess potential modulation of precursor proliferation by 22q11 cell cycle regulatory genes expressed maximally during cortical neurogenesis in the ventricular/subventricular zone. 3.) We will determine whether cortical projection neuron synapse formation and process growth is compromised by diminished 22q11 gene dosage. We evaluate roles of 22q11 genes expressed maximally during cortical synaptogenesis, and whose localization and function implicates them in mitochondrial regulation of metabolism. Our results will establish whether diminished 22q11 gene dosage compromises specification, genesis, and synapse formation for cortical projection neurons. Thus, we will provide an outline of cellular and molecular mechanisms that can contribute to cortical pathogenesis in the range of behavioral disorders associated with 22q11DS.

Public Health Relevance

There is still little understanding of the relationship between genetic mutations and devastating behavioral disorders including autism, mental retardation, attention deficit/hyperactivity disorder (ADHD), mood disorders, and schizophrenia. This project focuses on a mutation that eliminates one out of two copies of a small number of genes on chromosome 22 resulting in a disorder known as DiGeorge, Velo-cardio-facial, or 22q11 Deletion Syndrome in which patients are at highly increased risk for these neurological and psychiatric diseases. The same mutation can be modeled in mice, and one can identify how reduced levels of this relatively small (32-50) set of genes disrupt brain development or function. Thus, our studies help explain how a specific mutation can lead to changes in brain development and function that may underlie autism, mental retardation, ADHD, mood disorders and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042182-11
Application #
8446207
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2002-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
11
Fiscal Year
2013
Total Cost
$292,890
Indirect Cost
$105,740
Name
George Washington University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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