Protein restriction during pregnancy alters Cdkn1c silencing, dopamine circuitry and offspring behaviour without changing expression of key neuronal marker genes

Prodani, Chiara, Irvine, Elaine E., Sardini, Alessandro, Gleneadie, Hannah J., Dimond, Andrew, Van de Pette, Mathew, John, Rosalind ORCID: https://orcid.org/0000-0002-3827-7617, Kokkinou, Michelle, Howes, Oliver, Withers, Dominic J., Ungless, Mark A., Merkenschlager, Matthias and Fisher, Amanda G. 2024. Protein restriction during pregnancy alters Cdkn1c silencing, dopamine circuitry and offspring behaviour without changing expression of key neuronal marker genes. Scientific Reports 14 (1) , 8528. 10.1038/s41598-024-59083-7

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Abstract

We tracked the consequences of in utero protein restriction in mice throughout their development and life course using a luciferase-based allelic reporter of imprinted Cdkn1c. Exposure to gestational low-protein diet (LPD) results in the inappropriate expression of paternally inherited Cdkn1c in the brains of embryonic and juvenile mice. These animals were characterised by a developmental delay in motor skills, and by behavioural alterations indicative of reduced anxiety. Exposure to LPD in utero resulted in significantly more tyrosine hydroxylase positive (dopaminergic) neurons in the midbrain of adult offspring as compared to age-matched, control-diet equivalents. Positron emission tomography (PET) imaging revealed an increase in striatal dopamine synthesis capacity in LPD-exposed offspring, where elevated levels of dopamine correlated with an enhanced sensitivity to cocaine. These data highlight a profound sensitivity of the developing epigenome to gestational protein restriction. Our data also suggest that loss of Cdkn1c imprinting and p57KIP2 upregulation alters the cellular composition of the developing midbrain, compromises dopamine circuitry, and thereby provokes behavioural abnormalities in early postnatal life. Molecular analyses showed that despite this phenotype, exposure to LPD solely during pregnancy did not significantly change the expression of key neuronal- or dopamine-associated marker genes in adult offspring.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	15 April 2024
Date of Acceptance:	7 April 2024
Last Modified:	15 Apr 2024 10:48
URI:	https://orca.cardiff.ac.uk/id/eprint/167940

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