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

Abstract

The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5-to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for ''diseases of cortical connectivity'' thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbuminlabeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism. psychiatric disease T he neurodevelopmental hypothesis for diseases of cortical connectivity, initially proposed for schizophrenia (1), and later extended to autism spectrum disorders (2), suggests that anomalous cortical development underlies behavioral pathology. Despite inferred relationships between suspect developmental mechanisms, neuroanatomical or functional changes in patients, and postmortem cortical pathology, to our knowledge, there are no known direct links between specific cortical developmental mechanisms and pathogenesis. The near impossibility of prospective analyses in at-risk human fetuses further complicates rigorous evaluation of the hypothesis. Thus, the hypothesis may be more effectively evaluated in animal models of genetic or environmental risk for relevant diseases. In humans, 22q11 deletion/DiGeorge syndrome (22q11DS) confers the highest known genetic risk for schizophrenia (Ϸ30%) (3, 4), increased susceptibility for autism spectrum disorders (Ϸ25%) (5), and vulnerability for additional behavioral and learning disabilities (Ͼ60%) (5). Brain imaging in 22q11DS patients shows consistent anatomical defects, including reduced cortical gray matter and polymicrogyria (6-8), and postmortem analysis indicates cellular pathology associated with developmental defects including periventricular heteropias (9). We found that diminished 22q11 gene dosage in a 22q11DS mouse model compromises specific cortical neural stem cells, basal progenitors, and alters frequency and distribution of cortical projection neurons and GABAergic interneurons. These phenotypes suggest a link between a genomic lesion, altered cortical development, and subsequent changes in cortical circuitry that likely intensify risk for behavioral diso...

Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome

“…Thus, in 22q11.2DS, the available evidence indicates that cortical circuits are compromised and GABAergic interneurons are altered. We now report in the LgDel mouse-in which recent studies (18)(19)(20) suggest that cortical circuit assembly and function is compromised-a mechanistic relationship between diminished 22q11.2 dosage and a key molecular pathway that regulates interneuron migration during cortical development. LgDel interneuron phenotypes reflect interneuron-specific disruption of cytokine receptor Cxcr4, which has been shown to influence placement, migratory trajectory, and motility of these cells during cortical development (21)(22)(23)(24)(25).…”

“…Our previous work indicates that interneuron distribution is altered in the LgDel cortex, with an apparent shift of parvalbumin cells toward more superficial layers at the expense of deeper layers (18). To determine whether this defect is similar to those associated with other mutations that alter laminar distribution of interneurons (22,26,27), we evaluated the frequency and laminar distribution of molecularly distinct interneuron classes in the LgDel mouse.…”

“…Samples were hybridized to the mouse gene 1.0 ST array (Affymetrix). cDNA synthesis reactions were conducted as previously described (18). qPCR was conducted on a CFX384 thermal cycler using EvaGreen reagent (BioRad).…”

“…4H), consistent with a previous report of elevated expression in cardiac primordia in the Df1 22q11.2DS model (31). Counting boxes (600-μm wide and divided into equidistant bins) spanning the cortex between the pial surface and white matter tract were analyzed in coronal brain sections as described previously (18). (A) Parvalbumin cells are significantly redistributed (ANOVA, n = 5 per genotype; significant differences comparing bins between genotypes determined by LSD test, P = 0.05 at bin 3 and 0.0017 at bin 5; error bars represent SEM) but not for the other primarily MGE-derived interneuron subtype, somatostatin (B).…”

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

“…22q11DS mouse models present with a loss of glutamatergic synapses, decreased spine density, decreased CA1 pyramidal neuron complexity and reduced neurogenesis in the subventricular zone. The same mice show behavioural abnormalities in PPI, hyperlocomotion, fear conditioning and working memory [89][90][91][92][93][94] . 22q11DS is the only confirmed recurrent structural mutation associated with schizophrenia identified to date 95 .…”