Abstract
The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.
Highlights
The dopaminergic (DA) system plays a central role in key brain functions including voluntary movement, cognition, motivation, and reward behaviour [1,2,3]
After confirming the expression of HOTAIRM1 in SHSY5Y cells and small interfering RNA (siRNA) efficiency (Figure S1), we used retinoic acid (RA) to induce the differentiation of cells into DA neurons
We first knocked down the levels of HOTAIRM1 in SHSY5Y cells using siRNA against HOTAIRM1 for 24 h and differentiated the cells for 48 h in the presence of RA (Figure 1A)
Summary
The dopaminergic (DA) system plays a central role in key brain functions including voluntary movement, cognition, motivation, and reward behaviour [1,2,3]. Understanding the molecular mechanisms that regulate the maturation of the DA system will lay the groundwork for understanding how brain development shapes adult brain function and contributes to these disorders In both human and mouse embryos, almost all DA neurons are born early in gestation following similar temporal/spatial expressions of many DA transcription factors [8]. One particular lncRNA, the long intergenic non-coding RNA HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1), is present in adult human DA neurons and may regulate key dopaminergic factors. Studies on the post-mortem brain of individuals with cocaine addictions have found that HOTAIRM1 levels were correlated with the expression of genes coding for DA neuronal markers, including TH, the DA transporter (DAT), and the nuclear receptor related 1 protein (Nurr1) [29]. Our studies highlight a potential role for lncRNAs, including HOTAIRM1, as modulatory factors in early dopamine neuron development
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
