Thehoteimutation of medaka in the anti-Müllerian hormone receptor causes the dysregulation of germ cell and sexual development

Abstract

We previously performed mutant screens in the medaka for defects in gonadal development and identified a mutant of interest in this regard, which was designated as hotei (hot). This mutant manifests a number of remarkable phenotypic abnormalities including: (i) excessive proliferation of germ cells that initiates at around the hatching stage regardless of the genetic sex of the fish; (ii) initiation of premature meiosis in phenotypically male hot homozygotes; (iii) one-half of the hot-homozygous XY fish undergo sex reversal, which accompanies the expression of the femalecharacteristic aromatase gene in the somatic cells of the gonad; and (iv) in phenotypically female homozygotes, follicular development is arrested at an early stage. We have also performed genetic mapping, chromosome walking, and candidate gene sequencing analysis of hot and demonstrate that the underlying mutation occurs in the recently identified medaka anti-Mü llerian hormone (Amh) receptor type II (amhrII) gene. Moreover, this gene was found to be responsible for each of the hot phenotypes, as an amhrII transgene rescues these abnormalities. In addition, the amhrII gene is expressed in the somatic cells of the gonads of both sexes. The phenotypes of the hot homozygotes indicate that there are multiple regulatory functions of the AMH/AMHRII signaling system in the development of the gonad, including the sexdependent regulation of germ cell proliferation and follicular development. These presumably represent the basic roles of Amh, which precede Mü llerian duct evolution during phylogeny.gonad ͉ sex differentiation ͉ hotei mutant

Two distinct types of theca cells in the medaka gonad: Germ cell‐dependent maintenance of cyp19a1‐expressing theca cells

“…Cyp19a1 (ovarian-type aromatase) expression in the medaka has been analyzed with in situ hybridization at the level of tissues but not of cells. The cyp19a1 gene is expressed in the ventral region of the developing female gonads at 10 days post hatching (dph) and in the granulosa cells of the adult ovary (Suzuki et al, 2004;Kurokawa et al, 2007;Morinaga et al, 2007). However, it remains unknown how the cyp19a1-expressing cells develop during the course of gonadal development.…”

Anti-Müllerian hormone is a gonadal cytokine with two circulating forms and cryptic actions

“…AMH's role as an essential inducer of male sexual differentiation also predates the Müllerian duct. In some species of fish, AMH regulates the differentiation of the gonads into testes, and putatively determines testicular differentiation in birds (Smith & Sinclair 2004, Morinaga et al 2007, Wu et al 2010, Cutting et al 2013. In mammals, AMH does not affect gonad determination as XY AMH K/K individuals have testes (Behringer et al 1994, Josso et al 2012, although AMH is required for the normal cellular and biochemical development of the mammalian testis (Mishina et al 1996, Wu et al 2005.…”

“…In fish that do not have Müllerian ducts, AMH regulates the proliferation of germ cells in both sexes (Morinaga et al 2007). In all vertebrates, the production of AMH is from the cells that nourish, protect and regulate the germ cells: the Sertoli cells of the testes and the ovarian granulosa cells.…”

“…In all vertebrates, the production of AMH is from the cells that nourish, protect and regulate the germ cells: the Sertoli cells of the testes and the ovarian granulosa cells. This suggests that AMH has ancient roles in phylogeny as a regulator of germ cells (Morinaga et al 2007). AMH's role as an essential inducer of male sexual differentiation also predates the Müllerian duct.…”

Germline stem cells are critical for sexual fate decision of germ cells

“…AMH/MIS is essential for the regression of female reproductive organs, such as the upper vagina and oviduct. However, an analysis of the mutant of a type II receptor of AMH/MIS in medaka indicated AMH/MIS involvement in the regulation of the germline stem cell numbers, but not in the formation of reproductive organs 53, 54. This led to a hypothesis that the mammalian AMH/MIS acquired its role in the regression of female reproductive organs because the establishment of germline stem cells is dispensable during mammalian ovarian formation.…”