Developmental Inhibition of Long Intergenic Non-Coding RNA, HOTAIRM1, Impairs Dopamine Neuron Differentiation and Maturation.

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.