A comprehensive analysis of 22q11 gene expression in the developing and adult brain

Abstract

Deletions at 22q11.2 are linked to DiGeorge or velocardiofacial syndrome (VCFS), whose hallmarks include heart, limb, and craniofacial anomalies, as well as learning disabilities and increased incidence of schizophrenia. To assess the potential contribution of 22q11 genes to cognitive and psychiatric phenotypes, we determined the CNS expression of 32 mouse orthologs of 22q11 genes, primarily in the 1.5-Mb minimal critical region consistently deleted in VCFS. None are uniquely expressed in the developing or adult mouse brain. Instead, 27 are localized in the embryonic forebrain as well as aortic arches, branchial arches, and limb buds. Each continues to be expressed at apparently constant levels in the fetal, postnatal, and adult brain, except for Tbx1, ProDH2, and T10, which increase in adolescence and decline in maturity. At least six 22q11 proteins are seen primarily in subsets of neurons, including some in forebrain regions thought to be altered in schizophrenia. Thus, 22q11 deletion may disrupt expression of multiple genes during development and maturation of neurons and circuits compromised by cognitive and psychiatric disorders associated with VCFS.

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

“…Of the 22 22q11 genes expressed in the developing cerebral cortex (11), two genes (Tbx1 and Prodh) have emerged as candidates for many 22q11DS phenotypes, including behavioral anomalies (12,13). Nevertheless, we found no differences in basal progenitor frequency in either hemizygous Tbx1 or homozygous Prodh hypomorphic mice ( Fig.…”

“…This inf luence may extend beyond cortical development. These genes continue to be expressed in adult forebrain neurons and precursors (11), and may be part of larger cell-cycle regulatory networks that are differentially disrupted in schizophrenic and bipolar patients (46). Last, altered cell-cycle control in cortical precursors due to diminished 22q11 gene dosage may also contribute to increased tumorigenesis in 22q11 patients (47).…”

Catechol-O-methyl Transferase and Expression of Schizophrenia in 73 Adults with 22q11 Deletion Syndrome

“…There may be etiologic heterogeneity in general population samples obscuring subgroups that may have similar influences to those observed in 22q11DS. Given the ubiquitous nature of epistasis (Moore 2005), expression of any single allele in 22q11DS is likely to be modified by other genetic variants, possibly in COMT (Chen et al 2004) but likely elsewhere in the 22q11.2 deletion region (Maynard et al 2003), the rest of the genome, or both. Nongenetic factors could also be potential modifiers of genotypic effects.…”

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

“…ARVCF, along with TXNRD2, COMT, and most of the other genes in the VCFS 1.5 Mb (megabases) critical deletion region, is expressed in multiple regions of the early developing, adolescent, and mature mouse brain. 8 ARVCF is a member of the catenin family, a family which plays an important role in the formation of adherens junction complexes, which are thought to facilitate communication between the outside and the inside of a cell. 46 More recent work has confirmed that ARVCF is indeed part of the cadherin-catenin complex, and may modulate cadherin-mediated junctional structures and cell-cell adhesion in various cell types.…”

“…5 COMT resides within both neurons and glial cells in the brain, 6,7 but in the prefrontal cortex and striatum most COMT mRNAs are found in neurons in humans and mice. 7,8 There are two major forms of COMT, a soluble shorter form (S-COMT) found in the cytoplasm and a longer membrane-bound form (MB-COMT) found on the cytoplasmic side of the rough endoplasmic reticulum, [9][10][11][12] with the latter being the predominant form, B70% of total COMT protein, expressed in the brain. 13 In addition, catecholamines have a higher affinity, but a lower reaction velocity, with MB-COMT than with S-COMT, 14 making MB-COMT more effective at the lower physiological dopamine concentrations found in the brain, especially in the prefrontal cortex, 14,15 all of which points the greater importance of MB-COMT in the brain.…”