Modeling the Prader–Willi Syndrome-Associated Growth Phases in Snord116 KO Mice

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by distinctive developmental transition from neonatal hypotonia and poor feeding to progressive weight gain and, later, hyperphagia and obesity. The paternally expressed SNORD116 cluster is critical for postnatal growth, but how its deficiency impacts the progression of PWS remains unclear. Here, we analyzed the day-over-day growth rates for 351 mice with Snord116 deletion or altered Snord116 dosage, including their wild-type littermates, across both sexes and two genetic backgrounds. Snord116 expression increased markedly during early brain development. The Snord116-deficient mice exhibited a distinct three-stage growth trajectory: impaired growth until approximately P16, normalization between P17 and P21, followed by transient accelerated weight gain until approximately P30. Although growth rates subsequently normalized, the accumulated deficit was not fully compensated, and the adult Snord116KO mice remained smaller than the wild-type controls. These developmental transitions broadly parallel the early nutritional phases of human PWS, although the mice did not progress to exhibit persistent obesity-associated growth. Reactivation of the maternal Snord116 cluster partially rescued the growth phenotype, whereas activation of both parental alleles produced a modest growth advantage, which was most evident in the males. These findings identify early postnatal development as a critical window of Snord116-dependent growth regulation and provide a framework for investigating the mechanisms underlying PWS’s progression.