A chromosome 16p13.11 microduplication causes hyperactivity through dysregulation of miR-484/protocadherin-19 signaling

Abstract

Chromosome 16p13.11 microduplication is a risk factor associated with various neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, intellectual disabilities, developmental delay and autistic spectrum disorder. The underlying molecular mechanism of this genetic variation remained unknown, but its core genetic locus—conserved across mice and humans—contains seven genes. Here, we generated bacterial artificial chromosome-transgenic mice carrying a human 16p13.11 locus, and these mice showed the behavioral hyperactivity phenotype. We identified miR-484 as the responsible gene using a combination of expression and functional analyses. Mature miR-484 was expressed during active cortical neurogenesis, and overexpression of miR-484 decreased proliferation and increased neural progenitor differentiation in vivo. Luciferase screening identified the 3'-untranslated region of protocadherin-19 (Pcdh19) as a target of miR-484. The effect of miR-484 on neurogenesis was rescued by ectopic PCDH19 expression. These results demonstrate that miR-484 promotes neurogenesis by inhibiting PCDH19. Dysregulation of neurogenesis by imbalanced miR-484/PCDH19 expression contributes to the pathogenesis of 16p13.11 microduplication syndrome.

Regulation of neural circuit formation by protocadherins

“…In silico analysis identified the Pcdh19 3′UTR as a target for miR-484, and luciferase assays confirmed that miR-484 downregulates Pcdh19. Knockdown of Pcdh19 by shRNA delivered via in utero electroporation led to increased differentiation of radial glia into basal progenitors, consistent with Pcdh19 downregulation being the mechanism by which miR-484 acts [162]. Though it is not yet clear the extent to which Pcdh19 contributes to the various defects in 16p13.11 microduplication syndrome, its implication in this disorder further strengthens its link to neurological disease.…”

“…Finally, Pcdhs have been implicated in neuropsychiatric disorders including ASD, intellectual disabilities, and attention deficit hyperactivity disorder (ADHD) resulting from a duplication of the 16p13.11 locus, which contains 7 genes [162]. Fujitani et al [162] present evidence that a microRNA, miR-484, is the gene responsible for the behavioral phenotypes modeled in mice.…”

“…Fujitani et al [162] present evidence that a microRNA, miR-484, is the gene responsible for the behavioral phenotypes modeled in mice. Manipulation of miR-484 expression in cortical progenitors in vitro and in vivo indicated that it is required for the differentiation of radial glia into neurogenic basal progenitors.…”

The Cadherin Superfamily in Neural Circuit Assembly

“…Similar results have been obtained in the zebrafish, where loss of the δ2-Pcdh, pcdh19 , increases proliferation and the number of pcdh19 -expressing neurons in the optic tectum (Cooper et al 2015). The micro-RNA, miR-484, affects neurogenesis by regulating pcdh19 expression (Fujitani et al 2016). Increased levels of miR-484 cause hyperactivity in mice, which could be related to neurodevelopmental disorders associated with microduplications of this locus in humans.…”

Modeling Fragile X syndrome in neurogenesis: An unexpected phenotype and a novel tool for future therapies

“…[25][26][27] Indeed, premature neurogenesis has been associated to gross brain abnormalities in a thalassemia/mental retardation syndrome X-linked (ATRX), consistently with the microcephaly observed in patients affected by this disorder. 28,29 Similarly, accelerated cell cycle and overproduction of GABAergic inhibitory neurons were described in iPSC-derived brain organoids of Autism Spectrum Disorder (ASD) patients characterized by macrocephalia.…”