Deletion of the miR-379/miR-410 gene cluster at the imprintedDlk1-Dio3locus enhances anxiety-related behaviour

Abstract

The brain-specific miR-379/miR-410 gene cluster at the imprinted Dlk1-Dio3 domain is implicated in several aspects of brain development and function, particularly in fine-tuning the dendritic outgrowth and spine remodelling of hippocampal neurons. Whether it might influence behaviour and memory-related processes has not yet been explored at the whole organism level. We previously reported that constitutive deletion of the miR-379/miR-410 gene cluster affects metabolic adaptation in neonatal mice. Here, we examined the role of this cluster in adult brain functions by subjecting mice with the constitutive deletion to a battery of behavioural and cognitive tests. We found that the lack of miR-379/miR-410 expression is associated with abnormal emotional responses, as demonstrated by increased anxiety-related behaviour in unfamiliar environments. In contrast, spontaneous exploration, general locomotion, mood levels and sociability remained unaltered. Surprisingly, miR-379/miR-410-deficient mice also showed normal learning and spatial (or contextual) memory abilities in hippocampus-dependent tasks involving neuronal plasticity. Taken together, the imprinted miR-379/miR-410 gene cluster thus emerges as a novel regulator of the two main post-natal physiological processes previously associated with imprinted, protein-coding genes: behaviour and energy homeostasis.

A placental mammal‐specific micro RNA cluster acts as a natural brake for sociability in mice

“…In contrast, social recognition and object recognition were not affected in miR379-410 ko mice (Appendix Fig S3), indicating intact memory function. In addition, miR379-410 ko mice show reduced repetitive behaviour in the marble burying test ( Fig EV1F), and, in agreement with a previous study [23], increased anxiety-related behaviour in the open field and elevated plus maze (EPM) tests ( Fig EV1A-E). No differences in the homing test were observed ( Fig EV1G), suggesting intact olfaction in miR379-410 ko mice.…”

“…miR-124 was recently shown to partially restore social deficits associated with frontotemporal dementia [26], but in contrast to our study, this study relied on miRNA overexpression and focussed on the late adult stage. In addition, specific miRNAs, including miR-124 and the miR379-410 cluster, were shown to control anxiety-like behaviour [23,[27][28][29]. Intriguingly, the unusual combination of hypersocial and anxiety-like behaviour we observed in miR379-410 ko mice is present in patients suffering from two rare neurodevelopmental disorders, WBS [30] and AS [31].…”

The Role of the Prader-Willi Syndrome Critical Interval for Epigenetic Regulation, Transcription and Phenotype

“…The maternally expressed miRNAs (miR-379/miR-410) in the DLK1-DIO3 cluster are of particular importance for the understanding of the PWS phenotype and how it might be affected by IPW's regulatory role. The DLK1-DIO3 miRNAs are known to target over 400 genes, which are collectively associated with 67 human diseases, including various physiological anomalies and learning disabilities [42]. Deletion of the miR-379/miR-410 cluster in mouse models leads to increased anxiogenic behavior, as well as with disturbances in metabolic control and homeostasis maintenance [42,43].…”

“…The DLK1-DIO3 miRNAs are known to target over 400 genes, which are collectively associated with 67 human diseases, including various physiological anomalies and learning disabilities [42]. Deletion of the miR-379/miR-410 cluster in mouse models leads to increased anxiogenic behavior, as well as with disturbances in metabolic control and homeostasis maintenance [42,43]. These phenotypic outcomes are comparable with the physiological and behavioral phenotypes observed in patients and mouse models carrying a deletion of the PWS-cr interval [8,11,16,24].…”

Imprinted maternally-expressed microRNAs antagonize paternally-driven gene programs in neurons

“…Maternal inheritance of miR-379/410 deletion resulted in hypoglycemia immediately after birth (Labialle et al, 2014), suggesting these miRNAs control metabolic physiology during early development. Adult mice with maternal miR-Whipple | 3 379/410 deletion display anxiety-related behaviors and increased sociability, perhaps due to alterations in synaptic signaling (Lackinger et al, 2018;Marty et al, 2016). One miRNA from the cluster, miR-134-5p, localizes to the synapse and regulates dendritic spine size through translational repression of Limk1 and Pum2 (Fiore et al, 2009;Schratt et al, 2006).However, relatively few targets of this large miRNA cluster have been identified, and molecular understanding of how these miRNAs may coordinately regulate cellular programs is lacking.…”