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Enhancing Neuronogenesis and Counteracting Neuropathogenic Gene Haploinsufficiencies by RNA Gene Activation

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RNA Activation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 983))

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Abstract

Small activating RNAs (saRNAs), targeting endogenous genes and stimulating their transcription, are a promising tool for implementing a variety of neurotherapeutic strategies. Among these there is the stimulation of select histogenetic subroutines for purposes of cell-based brain repair, as well as the therapeutic treatment of gene expression deficits underlying severe neurological disorders.

We employed RNA activation (RNAa) to transactivate the Emx2 transcription factor gene in embryonic cortico-cerebral precursor cells. This led to enhanced self-renewal, delayed differentiation, and reduced death of neuronally committed precursors, resulting in a remarkable expansion of the neuronogenic precursors pool. These results are of paramount interest for purposes of gene-promoted brain repair. As such, RNAa makes therapeutic stimulation of neuronogenesis via Emx2 overexpression a feasible goal, preventing the drawbacks of exogenous gene copies introduction.

Moreover, we employed RNAa to achieve a gentle transactivation of the Foxg1 transcription factor gene, specifically in cortico-cerebral cells. This manipulation led to an appreciable biological outcome, while complying with endogenous gene tuning linked to early central nervous system regionalization and late activity of neocortical projection neurons. Foxg1-activating miRNAs stimulated RNApolII recruitment, possibly via Ago1. One of them worked promisingly in vivo. As such, RNAa can be a valuable approach for therapeutic treatment of the FOXG1-haploinsufficiency-linked variant of the Rett syndrome. Remarkably, hemizygosity for specific genes and polygenic chromosomal segments underlies a huge number of neuropathological entities for which no cure is presently available. Based on the results reported above, RNAa might be a simple and scalable approach for fixing this class of problems.

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Acknowledgments

The author thanks all collaborators who contributed to the two primary studies referred to in this chapter [11, 14], as well as the funding bodies providing financial support for their implementation (including Fondation Jérôme Lejeune grant 1176-MA2013A, Fondazione Telethon grant GGP13034, and SISSA intramurary funding to the author).

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  1. Lab of Cerebral Cortex Development, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, 34136, Trieste, Italy

    Antonello Mallamaci

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Correspondence to Antonello Mallamaci .

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  1. Laboratory of Molecular Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Long-Cheng Li

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Mallamaci, A. (2017). Enhancing Neuronogenesis and Counteracting Neuropathogenic Gene Haploinsufficiencies by RNA Gene Activation. In: Li, LC. (eds) RNA Activation. Advances in Experimental Medicine and Biology, vol 983. Springer, Singapore. https://doi.org/10.1007/978-981-10-4310-9_2

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