Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory

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Potocki-Lupski syndrome (PTLS) is a genomic disorder associated with an ∽3 Mb duplication in 17p11.2. Clinical features include leanness, intellectual disability, autistic features and developmental deficits.RAI1gene dosage is associated with the PTLS phenotypes. To understand where and whenRai1overexpression is detrimental, we generated a mouse that over-expressesRai1conditionally in forebrain neurons (I-Rai1). Phenotypic characterization of I-Rai1 mice showed significant underweight, hyperactivity and impaired learning and memory ability compared with wild-type littermates. Doxycycline administration can turn off the transgene expression allowing the restoration ofRai1normal expression levels. When the transgene was turned off from conception to 3 months of age, no phenotypic differences were observed between I-Rai1 and their wild-type littermates. Surprisingly, we found that turning off the transgene expression before the onset of the phenotypes (1-3 months) or after the onset of the phenotypes (3-5 months) cannot prevent nor reverse the phenotypic outcomes. Our results indicate thatRai1dosage in forebrain neurons is critical during the development and is related to body weight regulation, activity levels and learning and memory.

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