Cell death and sexual differentiation of behavior: worms, flies, and mammals

Sex differences in the nervous system are found throughout the animal kingdom. Here, we discuss three prominent genetic models: nematodes, fruit flies, and mice. In all three, differential cell death is central to sexual differentiation and shared molecular mechanisms have been identified. Our knowledge of the precise function of neural sex differences lags behind. One fruitful approach to the ‘function’ question is to contrast sexual differentiation in standard laboratory animals with differentiation in species exhibiting unique social and reproductive organizations. Advanced genetic strategies are also addressing this question in worms and flies, and may soon be applicable to vertebrates.

Introduction

In many animal species, males and females live in different social worlds, or at least play according to different social rules. Sex differences are commonly seen in courtship, communication, copulatory behaviors, and the processing of opposite-sex sensory cues [1, 2, 3]. Neural sex differences presumably allow for such behavioral differences and, indeed, are being found throughout the animal kingdom. This review compares sexual differentiation of the nervous system in three major genetic models of neural development: the nematode (Caenorhabditis elegans), the fruit fly (Drosophila melanogaster), and the laboratory mouse (Mus musculus).

In principle, neural sex differences could result from differences in any of the major neurodevelopmental events: neurogenesis, migration, neurite outgrowth, the differentiation of chemical phenotype, or cell death. Interestingly, however, in all three species (C. elegans, D. melanogaster, and M. musculus), cell death is the best-understood cellular mechanism underlying sexual differentiation of neural tissue. This suggests that cell death may be a highly efficient strategy for building a sex-specific nervous system. Alternatively, we may know so much about this mechanism because differences in cell number are often easier to detect than more subtle changes in connectivity or gene expression. In either case, as we describe below, recent studies have provided a fine-grained molecular analysis of how sex differences in cell number develop in worms, flies, and mice. Cell death has also been linked to neural sex differences in other animals, such as birds and frogs [4, 5], although due to the more limited ability for genetic manipulation, our understanding of underlying molecular mechanisms is less complete for these species.

In contrast to the progress made in understanding the mechanisms of neuronal cell death, much less is known about the function of sex differences in neuron number. This is particularly true in mammals where neural circuits are extremely complex and sex differences tend to be quantitative rather than qualitative. One strategy for circumventing this problem is to study simpler nervous systems such as those of worms and flies, where cells can be individually identified and circuitry is better known. Another avenue for understanding the function of sex differences in mammals, especially those related to sociosexual behaviors, is to expand our world-view beyond laboratory rodents to include species with different social and reproductive strategies. A good example is recent studies on naked mole-rats, which are highly social, cooperatively breeding rodents that forego sexual differentiation of behavior or postpone it until well into adulthood [6, 7]. Here, we first review the basics of sex determination and differentiation in C. elegans, Drosophila and rodents. Next, examples of sex differences in cell number in each species are discussed, along with what is known about underlying molecular mechanisms and the role in sociosexual behavior. We conclude with ongoing efforts to understand the meaning of neural sex differences.