Temporal dissection of Rai1 function reveals brain-derived neurotrophic factor as a potential therapeutic target for Smith-Magenis syndrome

Haploinsufficiency of RAI1 is responsible for Smith-Magenis Syndrome (SMS), a childhood neurodevelopmental disorder associated with hyperphagia, obesity, and autistic features. We previously showed that constitutive inactivation of one or both copies of Rai1 in the germline or developing brain induces SMS-like neurobehavioral deficits and obesity in mice. By contrast, the postnatal function of Rai1 is unclear. Here, we globally deleted one or both copies of Rai1 during two postnatal developmental windows by generating an inducible Rai1 knockout mouse model. We found that delayed Rai1 deletion at 3 or 8 weeks of age had no effect on neurobehavioral functions but resulted in adult-onset obesity and decreased expression of brain-derived neurotrophic factor (Bdnf) in the hypothalamus. Remarkably, genetic overexpression of human Bdnf in Rai1 heterozygous mice reversed SMS-like obesity, hyperphagia, metabolic syndrome-like features, and hyposociability. Increasing Bdnf signaling in the paraventricular nucleus of the hypothalamus (PVH) or the ventromedial nucleus of the hypothalamus (VMH) was sufficient to mediate the anti-obesity effect. Our work identifies the function of Rai1 in different temporal windows after birth and provides in vivo evidence that increasing Bdnf signaling is therapeutically effective in a preclinical mouse model of SMS.