Non-coding RNAs Function on Olfactory Sensory Neuron Development

Xu, Wenjing (2021). Non-coding RNAs Function on Olfactory Sensory Neuron Development. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00012420

Abstract

Neuronal plasticity in the brain is greatly enhanced early in life, during a time window referred to as the critical period. Mechanisms underlying heightened plasticity in this early developmental period remain largely unknown.

Employing the murine olfactory sensory neuron (OSN) as a model, I identify the long non-coding RNA H19 as one important regulator of the developmental critical period. H19 is one of the most abundant transcripts in the early embryonic and neonatal olfactory epithelium. Although H19 knockout does not affect olfactory axon projection pattern, it affects plasticity during the critical period. H19 knockout mice are deficient in the ability to recover convergent axon projection following odorant exposure during the critical period. Transgenic expression of H19 in the OSNs disrupts the singular projection pattern of OSN axons. This effect is associated with the ability of H19 to influence the maturation of OSNs, and its ability to extend the lifespan of navigator OSNs, which exhibit dynamic axon growth during the critical period. In contrast, transgenic expression of H19 transcript without the embedded miR-675 does not affect the plasticity of OSN axon projection. These results suggest H19 regulates the olfactory neuron developmental plasticity through regulating miR-675 expression.

I also investigated the role of ADAR, an enzyme that is involved in RNA editing and circular RNAs biogenesis, in the developmental of olfactory system. Adar-deficient OSNs display impaired axon targeting for certain olfactory receptor (OR) types. Transgenic expression of Adar1La, but not the isoform Adar1p150, widely downregulates circular RNAs. However, only ectopic expression of Adar1p150 disrupts olfactory axon projection. It is associated with an increase in neuronal activity. These results indicate that Adar influences axon projection during development, but this influence is unlikely to depend on circular RNA.

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