The imprinted Zdbf2 gene finely tunes control of feeding and growth in neonates

Genomic imprinting refers to mono-allelic and parent-specific expression of a subset of genes. While long recognized for their role in embryonic development, imprinted genes have recently emerged as important modulators of postnatal physiology, notably through hypothalamic functions. Here, we report that the paternally expressed Zdbf2 gene is essential for controlling neonatal growth in mice. Zdbf2-KO neonates failed to fully activate hypothalamic circuits that stimulate appetite, and suffered milk deprivation and diminished circulating Insulin Growth Factor 1 (IGF-1). Consequently, only half of Zdbf2-KO pups survived the first days after birth and those surviving were smaller. Using models of loss, gain and parental inversion of Zdbf2 expression, we further demonstrated that Zdbf2 acts in a dose-sensitive but parent-of-origin-independent manner. This study demonstrates that precise imprinted gene dosage is essential for vital physiological functions at the transition from intra- to extra-uterine life, here the adaptation to oral feeding and optimized body weight gain.