Mkrn3-KO Mouse

Mkrn3, or makorin ring finger protein 3, is an imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-13). It plays a crucial inhibitory role in the reproductive axis, acting as a key regulator of pubertal onset [5]. The onset of puberty depends on a decrease in factors inhibiting the release of gonadotropin-releasing hormone (GnRH), and Mkrn3 is involved in this regulatory pathway.

Loss-of-function mutations in Mkrn3 have been identified in patients with central precocious puberty (CPP), making it the most common known genetic cause of this condition [1,4,5,6,7]. In mouse models, deletion of Mkrn3 in hypothalamic neurons led to significant changes in genes controlling hypothalamic development and plasticity. Mkrn3 deletion in female mice resulted in early puberty onset, increased dendritic spines in the arcuate nucleus, and affected the regulation of neurokinin B (NKB) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [2]. Also, MKRN3-mediated ubiquitination of Poly(A)-binding proteins (PABPs) affects the stability and translation of GNRH1 mRNA, controlling both transcriptional and post-transcriptional aspects of puberty initiation [3].

In conclusion, Mkrn3 is a key inhibitor of puberty onset. Its function is mainly revealed through the study of loss-of-function mutations in patients and gene knockout mouse models. These findings have important implications for understanding the etiology of central precocious puberty, providing insights into the genetic mechanisms underlying the normal and abnormal regulation of pubertal development.