The hotei mutation of medaka in the anti-Muellerian hormone receptor causes the dysregulation of germ cell and sexual development

摘要

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 female-characteristic 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-Muellerian 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 sex-dependent regulation of germ cell proliferation and follicular development. These presumably represent the basic roles of Amh, which precede Muellerian duct evolution during phylogeny.