Paternally expressed imprinted Snord116 and Peg3 regulate hypothalamic orexin neurons

Pace, M.; Falappa, M.; Freschi, A.; Balzani, E.; Berteotti, C.; Lo Martire, V.; Kaveh, F.; Hovig, E.; Zoccoli, G.; Cerri, M.; Amici, R.; Urbanucci, A.; Tucci, V.

doi:10.1101/820738

bioRxiv · 10.1101/820738

Paternally expressed imprinted Snord116 and Peg3 regulate hypothalamic orexin neurons

Pace, M.·Falappa, M.·Freschi, A.·Balzani, E.·Berteotti, C.·Lo Martire, V.·Kaveh, F.·Hovig, E.·Zoccoli, G.·Cerri, M.·Amici, R.·Urbanucci, A.·Tucci, V.

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Abstract

Imprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chromosome 15q11-q13, is characterised by hypothalamic insufficiency. Here, we investigate the role of the paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a novel role of this imprinted gene in the function and organisation of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely, the orexin (OX) and melanin concentrating hormone (MCH) systems. We observe that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScrm+/p-) are compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutants. Therefore, we propose that an imbalance between OX- and MCH-expressing neurons in the LH of mutants reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.\n\nHighlightsO_LISnord116 regulates neuronal activity in the lateral hypothalamus (LH), which is time-locked with cortical states of sleep.\nC_LIO_LILoss of Snord116 reduces orexin neurons in the LH and affects sleep homeostasis and thermoregulation in mice.\nC_LIO_LISnord116 and Peg3 independently control orexin expression in the LH.\nC_LIO_LIPaternally expressed alleles maximize the patrilineal effects in the control of REM sleep by the LH in mammals.\nC_LI

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Pace, M., Falappa, M., Freschi, A., Balzani, E., Berteotti, C., Lo Martire, V., Kaveh, F., Hovig, E., Zoccoli, G., Cerri, M., Amici, R., Urbanucci, A., Tucci, V.. 2019-10-28. Paternally expressed imprinted Snord116 and Peg3 regulate hypothalamic orexin neurons. https://doi.org/10.1101/820738

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