Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome.
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 parvalbumin-labeled 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.
Meechan
Daniel W
DW
Department of Cell and Molecular Physiology and Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Tucker
Eric S
ES
Maynard
Thomas M
TM
LaMantia
Anthony-Samuel
AS
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D002872:Chromosome Deletion; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D033481:Chromosomes, Mammalian / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D004062:DiGeorge Syndrome / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026801:Synteny; D020825:T-Box Domain Proteins / Q000235:genetics
C491876:Cdc45 protein, mouse; D018797:Cell Cycle Proteins; D006657:Histones; D010750:Phosphoproteins; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D019938:Cyclin D1