Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch

Abstract

In mammals and birds, sex differences in brain function and disease are thought to derive exclusively from sex differences in gonadal hormone secretions. For example, testosterone in male mammals acts during fetal and neonatal life to cause masculine neural development. However, male and female brain cells also differ in genetic sex; thus, sex chromosome genes acting within cells could contribute to sex differences in cell function. We analyzed the sexual phenotype of the brain of a rare gynandromorphic finch in which the right half of the brain was genetically male and the left half genetically female. The neural song circuit on the right had a more masculine phenotype than that on the left. Because both halves of the brain were exposed to a common gonadal hormone environment, the lateral differences indicate that the genetic sex of brain cells contributes to the process of sexual differentiation. Because both sides of the song circuit were more masculine than that of females, diffusible factors such as hormones of gonadal or neural origin also likely played a role in sexual differentiation.T heories of sexual differentiation in birds and mammals postulate different mechanisms for sexual differentiation of gonadal and nongonadal tissues (1). Gonadal sex is determined by sex chromosome gene(s). In mammals, the Y-linked SRY gene is expressed within cells in the undifferentiated gonadal ridge to induce testicular development (2). In contrast, sexual differentiation of nongonadal (somatic) tissues, such as the brain, is caused by sex differences in early gonadal hormones (3, 4). A key question is whether somatic sexual differentiation also involves cell-autonomous action of sex chromosome genes as occurs in gonadal differentiation.An exclusively hormonal theory of brain sexual differentiation has been challenged by studies of zebra finches (Taeniopygia guttata). Males, but not females, sing a courtship song. The male's neural song nuclei are much larger and have larger neurons (5). Treatment of hatchling females with estradiol induces more masculine neural development, and they sing (6), suggesting that estrogens derived from gonadal secretions normally induce masculine song system development in males. However, treatments with gonadal hormones do not completely sex-reverse females, and blocking testicular hormones in males does not prevent masculine development (1). Moreover, testicular tissue induced to develop in genetic females does not masculinize the song system (7). One explanation for these results is that sex chromosome genes are expressed differently within brain cells of the two sexes and act in a cell-autonomous fashion to cause differences in song system development (8).The discovery of a rare bilateral gynandromorphic zebra finch presented us with an opportunity to test this hypothesis, because cells on one half of its brain and body were genetically male and cells on the other half were genetically female. Because both halves of the brain developed in the same gonadal hormonal environment, a complete...

A genetically female brain is required for a regular reproductive cycle in chicken brain chimeras

“…The existence of cell-autonomous development of the brain has been observed in the gynandromorphic finch 18 , and cell-autonomous development of somatic cells has been clearly demonstrated in gynandromorphic chickens 9 . Our present results show a new type of autonomous development of neural cells in birds associated with sexual dimorphism of the brain E2 concentration.…”

“…Midbrain dopamine neurons show sexual dimorphism in rodents, and this is controlled directly by the SRY gene 16,17 . In naturally occurring gynandromorphic finches, the neural song circuit in the right hemisphere has a more masculine phenotype than that in the left hemisphere, despite the influence of steroid hormones, which should be identical on both sides 18 .…”

Sex determination: insights from the chicken

“…One recent study described a gynandromorphic zebra finch, which was ZW female on the left side and ZZ male on the right. (7) This bird showed expression of a candidate W-linked female determinant (ASW) only on the 'female side' of the brain. However, since no sex chromosome aneuploidy was involved, this bird does not shed light on the Z dosage versus dominant W hypotheses.…”

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…Another way in which mouse developmental genetics seems to differ with that of human embryos concerns the LR-bilateral separation of pigmentation patterns in CHILD syndrome that occurs in man (Happle, 2002(Happle, , 2006 but is highly mosaic in mice, even though all of the other important features of this disease are present (Konig et al, 2000). The difference here may be profound precisely because a clean midline separation resulting from a nondisjunction/inactivation event at very early cleavage stages (as observed in bird gynandromorphs [Hutt, 1949;Agate et al, 2003;Levin, 2006]) suggests an extremely early origin of the midline, which may be true in many amniotes but not in mice.…”