Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions

International audienceAbstract Puberty is a critical period of development regulated by genetic, nutritional, and environmental factors. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP). To date, MKRN3 mutations are the most common known genetic cause of CPP. MKRN3 is a member of the makorin family of ubiquitin ligases, together with MKRN1 and MKRN2. The Mkrn genes have been identified in both vertebrates and invertebrates and show high evolutionary conservation of their gene and protein structures. While the existence of Mkrn orthologues in a wide spectrum of species suggests a vital cellular role of the makorins, their role in puberty initiation and endocrine functions is just beginning to be investigated. In this review, we discuss recent studies that have shown the involvement of Mkrn3 and other makorins in the regulation of pubertal development and other endocrine functions, including metabolism and fertility, as well as their underlying mechanisms of action

Le récepteur neural des œstrogènes bêta : Un nouvel acteur dans la maturation pubertaire femelle

International audienceLa puberté est une période critique du développement qui permet la transition entre l’enfance et l’adolescence. Elle se caractérise par l’augmentation des niveaux d’hormones gonadiques, l’apparition des caractères sexuels secondaires et l’acquisition de la capacité à se reproduire. Le déclenchement de la puberté est régulé par de nombreux facteurs. Des études épidémiologiques ont montré que 50 à 80 % des variations de l’âge de la puberté sont déterminés par des facteurs génétiques. Il est également établi que des facteurs environnementaux, comme les conditions socio-économiques, la nutrition, le stress, ou encore l’exposition à des perturbateurs endocriniens, jouent un rôle important dans le déclenchement de la puberté. Aujourd’hui, l’observation l’observation d’une avancée progressive de l’âge de la puberté chez les filles à travers le monde, soulève une forte inquiétude. Les causes de cette avancée ne sont pas clairement établies mais l’augmentation de l’obésité infantile et l’exposition grandissante à des polluants environnementaux y contribueraient fortement. Du fait des effets délétères que peut avoir une perturbation de l’âge de la puberté sur les fonctions de reproduction, mais également sur d’autres fonctions physiologiques comme les fonctions cardiovasculaires, métaboliques, ou encore psychologiques, il est devenu essentiel de comprendre les mécanismes mis en jeu dans le déclenchement de la puberté

Rôle du récepteur β des œstrogènes dans les comportements sociaux et émotionnels chez la souris mâle

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Elucidating the role of MKRN3 in puberty initiation using a model of hypothalamic neurons differentiated from human induced pluripotent stem cells

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Hypothalamic Overexpression of Makorin Ring Finger Protein 3 Results in Delayed Puberty in Female Mice

Abstract Makorin ring finger protein 3 (MKRN3) is an important neuroendocrine player in the control of pubertal timing and upstream inhibitor of gonadotropin-releasing hormone secretion. In mice, expression of Mkrn3 in the hypothalamic arcuate and anteroventral periventricular nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if the persistence of hypothalamic Mkrn3 expression peripubertally would result in delayed puberty. Female mice that received neonatal bilateral intracerebroventricular injections of a recombinant adeno-associated virus expressing Mkrn3 had delayed vaginal opening and first estrus compared with animals injected with control virus. Subsequent estrous cycles and fertility were normal. Interestingly, male mice treated similarly did not exhibit delayed puberty onset. Kiss1, Tac2, and Pdyn mRNA levels were increased in the mediobasal hypothalamus in females at postnatal day 28, whereas kisspeptin and neurokinin B protein levels in the arcuate nucleus were decreased, following Mkrn3 overexpression, compared to controls. Cumulatively, these data suggest that Mkrn3 may directly or indirectly target neuropeptides of Kiss1 neurons to degradation pathways. This mouse model suggests that MKRN3 may be a potential contributor to delayed onset of puberty, in addition to its well-established roles in central precocious puberty and the timing of menarche

Effects of neural estrogen receptor beta deletion on social and mood-related behaviors and underlying mechanisms in male mice

International audienceEstradiol derived from neural aromatization of testosterone plays a key role in the organization and activation of neural structures underlying male behaviors. This study evaluated the contribution of the estrogen receptor (ER) β in estradiol-induced modulation of social and mood-related behaviors by using mice lacking the ERβ gene in the nervous system. Mutant males exhibited reduced social interaction with same-sex congeners and impaired aggressive behavior. They also displayed increased locomotor activity, and reduced or unaffected anxiety-state level in three paradigms. However, when mice were exposed to unescapable stress in the forced swim and tail suspension tests, they spent more time immobile and a reduced time in swimming and climbing. These behavioral alterations were associated with unaffected circadian and restraint stress-induced corticosterone levels, and unchanged number of tryptophan hydroxylase 2-immunoreactive neurons in the dorsal raphe. By contrast, reduced mRNA levels of oxytocin and arginine-vasopressin were observed in the bed nucleus of stria terminalis, whereas no changes were detected in the hypothalamic paraventricular nucleus. The neural ERβ is thus involved to different extent levels in social and mood-related behaviors, with a particular action on oxytocin and arginine-vasopressin signaling pathways of the bed nucleus of stria terminalis, yet the involvement of other brain areas cannot be excluded