![]() Emc10 is a prenatally biased gene with high expression in embryonic life that gradually subsides after birth 7, a developmental pattern of expression conserved between mice, humans and nonhuman primates 19. Emc10 encodes for a component of the ER membrane complex (EMC), which promotes membrane insertion and maturation of a subset of polytopic and tail-anchored membrane proteins including neurotransmitter receptors, channels, and transporters 11– 18. Reduction of the miR-185 levels and to a lesser degree of miRNAs residing outside the deletion (such as miR-485 7) result in a de-repression of Emc10, whose expression is under the repressive control of miRNAs 7. The Df(16)A +/– related miRNA dysregulation is due to (i) hemizygosity of Dgcr8, a component of the “microprocessor” complex that is essential for miRNA production 10 and (ii) hemizygosity of miRNA genes residing within the deletion, including mir185. Our molecular analysis of the Df(16)A +/– strain provided compelling evidence for abnormal processing of brain enriched microRNAs (miRNAs) 5, 7. Increased brain expression of Emc10 is recapitulated in Df(16)A +/− primary neurons 8 as well as in mouse models of the more common 3Mb 22q11.2 deletion 9. Comprehensive RNA profiling of Df(16)A +/– mice found that postnatal elevation in the expression of the Mirta22/Emc10 gene (herein after referred to as Emc10) represents a key transcriptional effect of the 22q11.2 deletion 7. ![]() Previous work in a model of the 22q11.2 deletion, carrying a hemizygous 1.3-Mb deficiency on mouse chromosome 16, which is syntenic to the 1.5Mb 22q11.2 deletion described a distinct behavioral and cognitive profile 5, 6. 22q11.2 deletions are also one of the strongest genetic risk factors for schizophrenia (SCZ) 4. The observations that elevated EMC10 expression is deleterious in 22q11.2 deletion carriers and that sustained elevation of EMC10 throughout the adult life can interfere with neural processes point to manipulations of EMC10 levels and downstream targets as a specific venue to ameliorate or even prevent disease progression in 22q11.2 deletion syndrome.Īdults and children with the 22q11.2 Deletion Syndrome (22q11.2DS) demonstrate cognitive, social and emotional impairments 1– 3. Moreover, using injection of Antisense Oligonucleotides, we demonstrate that normalization of Emc10 levels in adult mouse brain rescues social memory deficits. Here we show that EMC10 expression is elevated in hiPSC-derived neurons from 22q11.2 deletion carriers and that reduction of EMC10 levels restores defects in neurite outgrowth and calcium signaling. EMC10 is a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. Up-regulation of Mirta22/Emc10 is a major transcriptional effect of the 22q11.2-associated microRNA dysregulation and underlies key cellular as well as behavioral deficits.
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