title: Cortical Development Requires Mesodermal Expression of Tbx1, a Gene Haploinsufficient in 22q11.2 Deletion Syndrome.
abstract: In mammals, proper temporal control of neurogenesis and neural migration during embryonic development ensures correct formation of the cerebral cortex. Changes in the distribution of cortical projection neurons and interneurons are associated with behavioral disorders and psychiatric diseases, including schizophrenia and autism, suggesting that disrupted cortical connectivity contributes to the brain pathology. TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS), a chromosomal deletion disorder characterized by a greatly increased risk for schizophrenia. We have previously shown that Tbx1 heterozygous mice have reduced prepulse inhibition, a behavioral abnormality that is associated with 22q11.2DS and nonsyndromic schizophrenia. Here, we show that loss of Tbx1 disrupts corticogenesis in mice by promoting premature neuronal differentiation in the medio-lateral embryonic cortex, which gives rise to the somatosensory cortex (S1). In addition, we found altered polarity in both radially migrating excitatory neurons and tangentially migrating inhibitory interneurons. Together, these abnormalities lead to altered lamination in the S1 at the terminal stages of corticogenesis in Tbx1 null mice and similar anomalies in Tbx1 heterozygous adult mice. Finally, we show that mesoderm-specific inactivation of Tbx1 is sufficient to recapitulate the brain phenotype indicating that Tbx1 exerts a cell nonautonomous role in cortical development from the mesoderm.
authors.affiliation: Institute of Genetics and Biophysics "ABT", CNR, 80131 Naples, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Flore
authors.affiliation: Institute of Genetics and Biophysics "ABT", CNR, 80131 Naples, Italy.|Bio-Ker srl, c/o Institute of Genetics and Biophysics "ABT", CNR, 80131 Naples, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cioffi
authors.affiliation: Institute of Genetics and Biophysics "ABT", CNR, 80131 Naples, Italy.
authors.forename: Marchesa
authors.initials: M
authors.lastname: Bilio
authors.affiliation: Institute of Genetics and Biophysics "ABT", CNR, 80131 Naples, Italy.|Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Illingworth
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006579:Heterozygote; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D013003:Somatosensory Cortex / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; C102938:Neurog2 protein, mouse; C491573:Tbx1 protein, mouse
keywords: 22q11.2 deletion syndrome; S1 cortex; Tbx1; animal model; cortical development