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MicroRNA Target Fingered in 22q11.2 Deletion Syndrome

18 January 2013. A report published January 17 in Cell sheds light on the contribution of microRNAs (miRNAs) to 22q11.2 deletion syndrome, a genetic predictor of schizophrenia. The study, led by Maria Karayiorgou and Joseph Gogos, both of Columbia University in New York, finds dramatic reductions in miR-185 expression in a mouse model of the syndrome and shows that a resulting upregulation in the neuronal gene 2310044H10Rik/Mirta22 produces altered dendrite and spine formation.

22q11.2 deletion syndrome, in which a portion of chromosome 22 has been removed, is characterized by birth defects and learning disabilities. Abnormalities in chromosome 22 are also thought to be involved in schizophrenia, since around 30 percent of the deletion carriers go on to develop the illness in adolescence or adulthood (see SRF related news story).

Gogos and Karayiorgou have developed a mouse model of 22q11.2 deletion syndrome, the Df(16)A+/- mouse, which closely mimics the human deletion of 1.5 Mb (see SRF related news story). Previous studies of this mouse line have indicated alterations in hippocampal dendritic spines, as well as alterations in the processing of microRNAs (miRNAs), small, noncoding RNAs that regulate mRNA expression (see SRF related news story; Xu et al., 2010). The altered miRNA expression is thought to be due, at least in part, to loss of one copy of the DGCR8 gene, a critical component of miRNA production (see SRF related news story).

Reduced miR-185 in Df(16)A+/- mice
In the current study, first author Bin Xu and colleagues observed that miR-185 expression is reduced by 70-80 percent in the hippocampus and prefrontal cortex of Df(16)A+/- mice during development and in adulthood. Notably, this reduction is much larger than both what is predicted by the 50 percent reduction in DGCR8 gene dosage and what is observed in DGCR8 mutant mice, suggesting that the effect extends beyond DGCR8. Since the miR-185 gene is also located within the deleted region of Df(16)A+/- mice, it is likely that hemizygosity of the gene itself also contributes to the reduction in miR-185 expression.

A transcriptional profile analysis revealed that the gene 2310044H10Rik is upregulated during postnatal development and adulthood in Df(16)A+/- mice. Two miRNA target site prediction programs indicated that binding sites for miR-185 are within the 3’ untranslated region (UTR) of 2310044H10Rik, suggesting that increased expression of 2310044H10Rik in Df(16)A+/- mice may be a consequence of miR-185 downregulation.

To investigate whether 2310044H10Rik is indeed under the control of miR-185, the authors transfected an miR-185 precursor mimic into Df(16)A+/- primary neuronal cultures. They observed a reduction in 2310044H10Rik in transfected cells, confirming that the gene is repressed by miR-185. Subsequent experiments demonstrated that this repression is dependent on the 3’ UTR of 2310044H10Rik. Two other miRNAs—miR-485 and miR-491—were also demonstrated to play smaller roles in the upregulation of 2310044H10Rik in Df(16)A+/- mice, suggesting that decreases in both miR-185 and DGCR8 contribute to the increase in 2310044H10Rik. Based on their confirmation of repression by miRNAs, the authors renamed the gene Mirta22, which stands for miRNA target of the 22q11.2 microdeletion.

Meet Mirta22
Mirta22 encodes a protein of unknown function that is elevated by approximately 25 percent in Df(16)A+/- mice. Immunocytochemistry revealed that it is distributed throughout the brain, and is found primarily in the Golgi apparatus and dendritic shafts of neurons.

Consistent with a report that miRNAs preferentially target genes in the same functional group (Tsang et al., 2010), the authors used functional annotation clustering analysis to determine that a Golgi-related gene cluster was the major target of miR-185. However, the reduction of miR-185 in Df(16)A+/- mice was associated with only a mild alteration of Golgi-related genes, with only four of 159 Golgi-related probe sets included in the top 100 dysregulated genes in the mouse hippocampus.

Since Mirta22 is localized to the Golgi and dendritic shafts of neurons, Xu and colleagues reasoned that its upregulation by miR-185 may contribute to the impaired dendrite and spine formation observed in Df(16)A+/- mice (Mukai et al., 2008). Consistent with this idea, an increase in Mirta22 produced dendritic abnormalities, including diminished complexity, spine density, and spine width in wild-type neuronal cultures, while a knockdown of Mirta22 reversed these deficits in Df(16)A+/- cultures. Similar results on dendrites were obtained after miR-185 downregulation in wild-type cultures and upregulation in Df(16)A+/- cultures. The effect of Mirta22 also held up in vivo. After crossing Mirta22 mutant and Df(16)A+/- mice, the researchers observed that the addition of the Mirta22 mutation could reverse the deficits in hippocampal dendritic complexity and spine formation in the Df(16)A+/- mice.

In summary, a reduction in miR-185 in a mouse model of 22q11.2 deletion syndrome produces elevated levels of Mirta22 that alter dendrite and spine formation. According to the authors, their study identifies elevated Mirta22 as β€œthe most robust gene change resulting from the 22q11.2 microdeletion, as well as the major downstream transcriptional effect of the 22q11.2-associated miRNA dysregulation.”—Allison A. Curley

Xu B, Hsu P-K, Stark KL, Karayiorgou M, Gogos JA. Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell 2013. 152: 762-275. Abstract

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