title: Allelic reduction of Dlx5 and Dlx6 results in early follicular depletion: a new mouse model of primary ovarian insufficiency.
abstract: Primary ovarian insufficiency (POI) is characterized by the loss of ovarian function before the age of 40 in humans. Although most cases of POI are idiopathic, many are familial, underlying a genetic origin of the disease. Mutations in genes involved in the control of steroidogenesis, such as NR5A1 (SF-1, Steroidogenic Factor 1), CYP17, CYP19A1 (aromatase), StAR (Steroidogenic Acute Regulatory), and the forkhead transcription factor FOXL2 have been associated with different forms of POI. In males, the homeobox transcription factors Dlx5 and Dlx6 are involved in the control of steroidogenesis through the activation of GATA4-induced-StAR transcription. Here, we analyze the potential involvement of Dlx5 and Dlx6 in female reproduction. To this end, we make use of an existing mouse model in which Dlx5 and Dlx6 are simultaneously disrupted. We show that: (i) allelic reduction of Dlx5 and Dlx6 in the mouse results in a POI-like phenotype, characterized by reduced fertility and early follicular exhaustion; (ii) in granulosa cell lines, a reciprocal regulation exists between Dlx5 and Foxl2; (iii) in the mouse ovary, allelic reduction of Dlx5/6 results in the upregulation of Foxl2. We propose that the mutual regulation between Dlx5/6 and Foxl2 and their opposite effects on StAR expression might contribute to determine the homeostatic control of steroidogenesis within the ovary. Dysregulation of this homeostatic control would result in abnormal follicular maturation and reduced fertility. Our results bring new elements to our conceptual model of follicle maturation and maintenance and provide new potential genetic targets for cases of familial POI.
authors.affiliation: Evolution des Régulations Endocriniennes, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Paris, France.
authors.forename: Kamal
authors.initials: K
authors.lastname: Bouhali
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dipietromaria
authors.forename: Anastasia
authors.initials: A
authors.lastname: Fontaine
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caburet
authors.forename: Ottavia
authors.initials: O
authors.lastname: Barbieri
authors.forename: Brice
authors.initials: B
authors.lastname: Bellessort
authors.forename: Marc
authors.initials: M
authors.lastname: Fellous
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Veitia
authors.forename: Giovanni
authors.initials: G
authors.lastname: Levi
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005298:Fertility / Q000235:genetics; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D023061:Gene Order; D006107:Granulosa Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000378:metabolism* / Q000473:pathology*; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: C501120:Dlx5 protein, mouse; C100597:Dlx6 protein, mouse; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins