Blurring the edges in vertebrate sex determination

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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.

Introduction

Across vertebrates, primary sex determination is defined as the decision within the bipotential gonad to develop as a testis or an ovary. Within the past decade, the traditional view of this process, in which a strict division is drawn between species that employ genetic mechanisms (genetic sex determination, GSD; e.g. mammals and birds) to determine sex and those that use environmental mechanisms (such as temperature-dependent sex determination, TSD; e.g. crocodiles), has been supplanted by the theory that GSD and TSD actually represent points on a continuum along which populations can and do shift, under selective pressure [1, 2, 3••]. This novel perspective is strengthened by the recent accumulation of empirical data suggesting that genetic elements influence systems that use TSD, and that functional or vestigial temperature sensitivity is present in organisms that employ GSD, even some with heteromorphic sex chromosomes [4•, 5•, 6•, 7••]. Additionally, many of the cellular processes, transcription factors, and signaling pathways involved in sex determination and gonadogenesis are conserved across vertebrates, implying that the underlying machinery may be similar despite modifications in the dominant upstream signal used. This perspective will be discussed in the present review, in the context of converging ideas about how sex-specific development of the gonads is initiated.

Section snippets

Rapid evolutionary transitions between sex-determining mechanisms

The methods of sex determination (e.g. GSD (XX/XY, ZZ/ZW, or homomorphy), TSD, polygenic, or density-dependent) used by many species of reptile, amphibian, and fish have been elucidated in recent years (Figure 1) [3••, 8, 9, 10]. When these are plotted onto a phylogenetic map, the evolutionary lability of sex determination is apparent within several major branches of the tree, where numerous transitions must have occurred to achieve the present diversity [3••]. Most of these inferred

Overriding GSD by hormones and temperature

Eutherian mammals, with XX/XY male heterogamety, comprise one of the most strictly GSD groups in the animal kingdom. Classic work in the mouse and human systems demonstrated that expression of the Y-chromosome-linked Sry gene in the supporting cell lineage leads to their differentiation as Sertoli cells and the adoption of the testis fate [16, 17]. In the absence of this upstream signal, ovarian development ensues. The evolution of both viviparity and endothermy in eutherian mammals required a

Thermosensitive gene expression in a GSD turtle

In TSD species, many genes known to be involved in sex determination or gonadogenesis show temperature-specific expression patterns during the temperature-sensitive period of development, before sex has been determined; however, the functional significance of these findings is not clear (e.g. [33, 34, 35•, 36, 37, 38]). For example, expression of DMRT1 in the red-eared slider turtle, Trachemys scripta, is elevated at the male-producing temperature as compared to the higher female-producing

Geographic pressures on TSD

The pivotal temperature (TP) for a TSD species is defined as the range of incubation temperatures that produce a 1:1 male to female sex ratio. In many species, temperatures below the TP will yield an increasingly male-biased ratio, and higher temperatures will generate more females (MF), though this pattern is often reversed (FM). While only one TP has been observed in many species, others exhibit a FMF pattern with two distinct transition points [7••]. It has been proposed that the existence

Evolutionary advantage of TSD

As TSD has been documented in a wide array of species, it must carry selective advantages in particular environments. Unfortunately, the longevity and delayed sexual maturity characteristic of most reptilian TSD species have made direct evaluations of reproductive fitness impractical. The Charnov–Bull model predicts that TSD should be favored if the fitness of (either or both) males and females is enhanced by development under a particular set of environmental conditions [40]. In their study of

Antagonistic pathways: a plastic system for evolutionary adaptation

The decision to develop as a male or female depends on whether the gonad develops as a testis or an ovary. In mammals, this decision rests on the fate of the supporting cell lineage, which either initiates differentiation as Sertoli (male) or follicle (female) cells. Fgf9 and Wnt4 act as mutually antagonistic signals that converge on Sox9 during sex determination to regulate the fate of the supporting cell lineage in mice [42•]. Both Fgf9 and Wnt4 are expressed in the bipotential gonad. Sry

Conclusions

In contrast to the high conservation of most developmental pathways across species from Drosophila to man, a stunning variety of mechanisms of sex determination exist within the animal kingdom. The distinction between genetically and environmentally based primary signals is beginning to blur as a result of the discovery of coincident thermal and genetic influences within single species, as well as the high degree of conservation in the genes governing gonadogenesis. The model of antagonistic

Conflict of interest

The authors declare no conflict of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Steve Munger and Leo DiNapoli for insightful comments and critical reading of the manuscript. Funding in the Capel laboratory is provided by the National Science Foundation (0317234) and the National Institutes of Health (HL63054 and HD39963).

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