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) [4]. It plays a crucial inhibitory role in the reproductive axis, specifically in regulating the onset of puberty [1,3,4]. The initiation of puberty depends on a decrease in factors inhibiting the release of gonadotropin-releasing hormone (GnRH), and Mkrn3 is part of this regulatory mechanism [4]. The gene shows ubiquitous expression in tissues across a broad spectrum of species, suggesting an important cellular role [1]. Genetic models, such as mouse models, have been valuable in studying Mkrn3's function.

In mouse models, deletion of Mkrn3 in hypothalamic neurons derived from human induced pluripotent stem cells led to significant changes in genes controlling hypothalamic development and plasticity [2]. Mkrn3 deletion in a mouse model also caused early puberty onset in female mice [2]. It was found that Mkrn3 deletion increased the number of dendritic spines in the arcuate nucleus without altering the morphology of GnRH neurons during postnatal development [2]. Additionally, neurokinin B (NKB) was identified as an Mkrn3 target, and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was also found to interact with Mkrn3 [2]. In another study, loss-of-function mutations in MKRN3 in patients with central precocious puberty (CPP) were identified, and in mice, the hypothalamic Mkrn3 mRNA expression pattern correlated with a putative inhibitory input on puberty initiation [4]. Also, MKRN3 was shown to be expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and to repress promoter activity of human KISS1 and TAC3, two key stimulators of GnRH secretion [5].

In conclusion, Mkrn3 is a key inhibitor of puberty onset. Through model-based research, especially using mouse models with Mkrn3 deletion or loss-of-function mutations, we have learned that Mkrn3 regulates pubertal initiation by affecting hypothalamic development and plasticity, interacting with various factors like NKB and IGF2BP1, and repressing the transcription of genes that stimulate GnRH secretion. These findings have significant implications for understanding the etiology of central precocious puberty [1,2,4,5].

References:

1. Palumbo, Stefania, Cirillo, Grazia, Aiello, Francesca, Miraglia Del Giudice, Emanuele, Grandone, Anna. 2022. MKRN3 role in regulating pubertal onset: the state of art of functional studies. In Frontiers in endocrinology, 13, 991322. doi:10.3389/fendo.2022.991322. https://pubmed.ncbi.nlm.nih.gov/36187104/

2. Naulé, Lydie, Mancini, Alessandra, Pereira, Sidney A, Abreu, Ana Paula, Kaiser, Ursula B. 2023. MKRN3 inhibits puberty onset via interaction with IGF2BP1 and regulation of hypothalamic plasticity. In JCI insight, 8, . doi:10.1172/jci.insight.164178. https://pubmed.ncbi.nlm.nih.gov/37092553/

3. Naulé, Lydie, Kaiser, Ursula B. 2020. Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions. In Seminars in reproductive medicine, 37, 166-173. doi:10.1055/s-0039-3400965. https://pubmed.ncbi.nlm.nih.gov/31972861/

4. Abreu, Ana Paula, Macedo, Delanie B, Brito, Vinicius N, Kaiser, Ursula B, Latronico, Ana Claudia. . A new pathway in the control of the initiation of puberty: the MKRN3 gene. In Journal of molecular endocrinology, 54, R131-9. doi:10.1530/JME-14-0315. https://pubmed.ncbi.nlm.nih.gov/25957321/

5. Abreu, Ana Paula, Toro, Carlos A, Song, Yong Bhum, Ojeda, Sergio, Kaiser, Ursula B. . MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. In The Journal of clinical investigation, 130, 4486-4500. doi:10.1172/JCI136564. https://pubmed.ncbi.nlm.nih.gov/32407292/