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

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Abstract
Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by distinctive developmental transition from neonatal hypotonia and poor feeding to pro-gressive weight gain and, later, hyperphagia and obesity. The paternally expressed SNORD116 cluster is critical for postnatal growth, but how its deficiency shapes this progression remains unclear. Here, we analyzed day-over-day growth rates in 351 mice carrying Snord116 deletion or altered Snord116 dosage, including wild-type littermates, across both sexes and two genetic backgrounds. Snord116 expression increased markedly during early brain development. 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. Alt-hough growth rates subsequently normalized, the accumulated deficit was not fully compensated, and adult Snord116KO mice remained smaller than wild-type controls. These developmental transitions broadly parallel early nutritional phases of human PWS, although mice did not progress to 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, most evident in males. These findings identify early postnatal development as a critical window of Snord116-dependent growth regulation and provide a framework for investigating mechanisms underlying PWS progression.

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