Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Abstract

NEAT1 is a highly and ubiquitously expressed long non-coding RNA (lncRNA) which serves as an important regulator of cellular stress response. However, the physiological role of NEAT1 in the central nervous system (CNS) is still poorly understood. In the current study, we addressed this by characterising the CNS function in the Neat1 knockout mouse model (Neat1 -/mice), using a combination of behavioural phenotyping, electrophysiology and expression analysis. RNAscope® in situ hybridisation revealed that in wild-type mice, Neat1 is expressed evenly across the CNS, with high expression in glial cells and low expression in neurons. Loss of Neat1 in mice results in an inadequate reaction to physiological stress manifested as hyperlocomotion and panic escape response. In addition, Neat1 -/mice display deficits in social interaction and rhythmic patterns of activity but retain normal motor function and memory. Neat1 -/mice do not present with neuronal loss, overt neuroinflammation or gross synaptic dysfunction in the brain. However, cultured Neat1 -/neurons are characterised by hyperexcitability and dysregulated calcium homeostasis, and stress-induced neuronal activity is also augmented in Neat1 -/mice in vivo. Gene expression analysis showed that Neat1 may act as a weak positive regulator of multiple genes in the brain. Furthermore, loss of Neat1 affects alternative splicing of genes important for the CNS function and implicated in neurological diseases. Overall, our data suggest that Neat1 is involved in stress signaling in the brain and fine-tunes the CNS functions to enable adaptive behaviour in response to physiological stress.

Expression and functions of long non-coding RNA NEAT1 and isoforms in breast cancer

“…51 This notion has now changed as several studies have been undertaken to more thoroughly investigate their physiology and behaviour at specific physiological circumstances. 21,[74][75][76][77][78][79][80] Most strikingly, female Neat1 ko mice are less fertile than wild type mice and have defects in postnatal mammary gland development that critically interferes with their ability to nurture offspring. 74,75 The compromised fertility may, at least partially, be explained by impaired corpus luteum formation and reduced secretion of progesterone.…”

“…77 Neat1 ko mice also display behavioural abnormalities that indicate defects within the central nervous system, and cultivated neurons from Neat1 ko mice are hyper excitable and have dysregulated calcium homeostasis. 78,79 NEAT1 is abnormally expressed in many cancers NEAT1 is upregulated in tumour cells compared to normal cells in a wide range of human solid cancers (recently reviewed in 10,[81][82][83] ). In most cases, elevated NEAT1 expression is associated with aggressive disease and poor clinical outcome.…”

Long Non-Coding RNA-Ribonucleoprotein Networks in the Post-Transcriptional Control of Gene Expression

“…Similar to MALAT1 , also NEAT1 recently proved to play an important role in modulating AS events. Shelkovnikova laboratory, taking advantage of a Neat1 knockout mouse model, demonstrated that the lncRNA controls the AS of a group of genes important for neuronal proliferation and differentiation, cell–cell interactions in the central nervous system (CNS), synaptogenesis, and axon guidance [ 23 ]. Interestingly, Neat1 also controls the AS of a group of RBPs including hnRNPA2B1, hnRNPH1, hnRNPD, hnRNPK, SRSF5, and SRSF7 [ 23 ].…”

“…Shelkovnikova laboratory, taking advantage of a Neat1 knockout mouse model, demonstrated that the lncRNA controls the AS of a group of genes important for neuronal proliferation and differentiation, cell–cell interactions in the central nervous system (CNS), synaptogenesis, and axon guidance [ 23 ]. Interestingly, Neat1 also controls the AS of a group of RBPs including hnRNPA2B1, hnRNPH1, hnRNPD, hnRNPK, SRSF5, and SRSF7 [ 23 ]. Neat1 knockout mice display a phenotype characterized by deficit in social interaction and rhythmic patterns of CNS activity [ 23 ].…”

“…Interestingly, Neat1 also controls the AS of a group of RBPs including hnRNPA2B1, hnRNPH1, hnRNPD, hnRNPK, SRSF5, and SRSF7 [ 23 ]. Neat1 knockout mice display a phenotype characterized by deficit in social interaction and rhythmic patterns of CNS activity [ 23 ]. Further evidence of the role of Neat1 in regulating AS derived from a recent study that demonstrated the interaction of the lncRNA with the multifunctional RBP KHSRP.…”