Available: 10/09/19, Expires: 06/30/21
Puberty is a remarkable time during which the body develops secondary sexual characteristics and becomes capable of reproduction. Puberty onset is due to a complex interplay of factors, including genetic influences. Mutations in disorders of puberty, including central precocious puberty (CPP) and delayed puberty, provide windows into understanding the neuroendocrine mechanisms of puberty and reproduction. The most common genetic cause of precocious puberty is due to loss-of-function mutations in a gene called Makorin Ring Finger Protein 3 (MKRN3. The function and regulation of MKRN3 are not well understood, but its protein structure suggests E3 ubiquitin ligase and RNA binding activities. Expression of Mkrn3 is high in the rodent hypothalamus and rapidly declines before puberty onset. Similarly, serum levels of MKRN3 in healthy children decline before the onset of puberty. This supports its role as the first inhibitor of puberty onset, hypothesized to act upstream of GnRH and/or its activators, such as kisspeptin.
The goal of this research project is to explore if alterations in Mkrn3 expression can similarly lead to delayed pubertal onset using innovative mouse models. Preliminary studies demonstrate a delayed puberty phenotype in wild type female mice injected intracerebroventricularly with a recombinant virus overexpressing Mkrn3. This current model will be used to explore MKRN3’s mechanism of action including its impact on known neuroendocrine players in reproduction. The use of this recombinant virus will be used to assess if it can also lead to hypogonadotropic hypogonadism postpubertally by bilateral stereotaxic injection into the rodent hypothalamus.
The technical aspects of these experiments may include experience in maintenance of a rodent colony, animal handling, assessment of rodent reproduction by physical exam, sample collection, RNA extraction, cDNA synthesis, quantitative PCR, western blot and immunocytochemistry. The results of this project to identify MKRN3’s targets of action are critical to understanding this key player in the neuroendocrine control of puberty and reproduction and has implications for future treatment of disorders of puberty and reproduction.