Blurring the edges in vertebrate sex determination

Abstract

Sex in vertebrates is determined by genetically or environmentally based signals. These signals initiate molecular cascades and cell-cell interactions within the gonad that lead to the adoption of the male or female fate. Previously, genetically and environmentally based mechanisms were thought to be distinct, but this idea is fading as a result of the unexpected discovery of coincident genetic and thermal influences within single species. Together with accumulating phylogenetic evidence of frequent transitions between sex-determining mechanisms, these findings suggest that genetic and environmental sex determination actually represent points on a continuum rather than discrete categories, and that populations may shift in one direction or the other in response to mutations or changing ecological conditions. Elucidation of the underlying molecular basis of sex determination in mice has yielded a bistable model of mutually antagonistic signaling pathways and feedback regulatory loops. This system would be highly responsive to changes in the upstream primary signal and may provide a basis for the rapid evolution of and transitions between different methods of sex determination.

Figure 1

Sex determination in extant vertebrates. Fish, amphibians, turtles, and lizards each exhibit more than one method of sex determination, which fall into genetic (GSD) and environmentally based categories. XX/XY and ZZ/ZW refer to male and female heterogametic systems, respectively, while homomorphy refers to GSD in the absence of differentiated sex chromosomes. Polygenic and density-dependent sex determination are characteristic of a subset of fish, and many reptiles and fish determine sex according to the incubation temperature of the egg (TSD). With the exception of eutherian mammals, most vertebrate embryos are susceptible to exogenous hormone-induced sex reversal. *Co-occurrence of TSD and GSD has been noted in several species of lizards. °Monotremes (i.e., platypus and echidna) have a complex arrangement of X and Y sex chromosomes, which assemble into a chain during meiosis.

Figure 2

Hypothetical evolutionary transition between GSD and TSD systems. A, Based on the mammalian model, the bipotential gonad is initially balanced between alternative fates by mutually antagonistic male and female factors. The appearance of a segregating, dominant allele of a key gene(s) in either the male or female pathway can fix a genetic mechanism. This may occur by gene duplication and evolution of a sex chromosome (as in the case of Sry in mammals or Dmy in medaka). B, Subsequent acquisition of a temperature-sensitive mutation in a female gene (e.g., aromatase) that increases expression or activity at a high temperature, may override the male factor and shift the balance towards the female pathway. C, At intermediate temperatures, the pathways will remain balanced, so that males and females are produced stochastically at equal frequencies. D, At a low temperature, the mutated female factor will be far from its thermal optimum, activity will drop, and the balance will shift towards the male pathway. Depending on the strength of the determining factor, the system may be more or less stable to perturbation by the appearance of new mutations. Selective pressure may favor changes that maintain a balanced sex ratio.

Figure 3

The decision to develop as a testis or ovary may originate in distinct gonad cell types in different vertebrates. For example, Sry is expressed in mammalian supporting cell precursors, leading to their differentiation as Sertoli cells, which then direct germ cells to enter mitotic arrest and steroidogenic precursors to differentiate as Leydig cells [17]. This cascade of cell-cell interactions and differentiation might also be initiated by expression of other male factors in the supporting cell precursors [12,43,53,54]. Alternatively, in other vertebrates, the decision might be made in other cell lineages. Upregulation of aromatase, a steroidogenic enzyme that converts testosterone to estrogen, in the steroidogenic precursors may allow these cells to induce ovarian development by a hormonal mechanism [reviewed in 55]. Similarly, mitotic proliferation of germ cells or entry into meiosis [56] could induce changes in the steroidogenic and supporting cell precursors that together initiate adoption of the female fate. Solid and dotted arrows represent demonstrated and putative cell-cell interactions, respectively.