Editors' ChoiceDevelopmental Biology

Digital Bias

Science Signaling  04 Oct 2011:
Vol. 4, Issue 193, pp. ec276
DOI: 10.1126/scisignal.4193ec276

Humans show gender-specific differences in the length ratio between the second finger (2D) and the fourth finger (4D). In women, the second finger tends to be the same length as or longer than the fourth finger, which results in a higher length ratio between 2D and 4D (2D:4D), whereas in men, the fourth finger tends to be longer than the second finger, which results in a lower 2D:4D. The 2D:4D ratio has been correlated to various sexually dimorphic traits (see commentary by Manning). To determine whether alterations in these ratios (2D:4D) reflect in utero exposure to testosterone, as has been presumed, Zheng and Cohn examined hind-leg development in CD-1 mice, a process that showed sexual dimorphism at embryonic day 17 (E17) in the right hind paw and at E21 in the left hind paw. When bound to ligand, the androgen receptor (AR) and estrogen receptor (ER) translocate to the nucleus to transcriptionally activate target genes. In E12.5 male and female mice, the AR showed nuclear localization in the cells of developing digits, and nuclear localization of the AR was higher in 4D than in 2D. By E14.5, the nuclear localization of AR was greater in male mouse 4D than in female mouse 4D. At the same developmental period, the abundance and nuclear localization of ERα was higher in 4D of both male and female mice than in 2D. The difference between AR activity in 4D compared with 2D was greatest in male mice; similarly, female mice showed a more pronounced difference in ERα activity in 4D compared with 2D. In male mice, genetic ablation of AR in the limb resulted in increased or feminized 2D:4D ratios, whereas ERα deficiency resulted in decreased or masculinized 2D:4D ratios. Treating pregnant female mice between E12.5 and E15.5 with the anti-androgen flutamide caused male offspring to have higher 2D:4D ratios, whereas treatment with dihydrotestosterone (DHT) caused female offspring to have lower 2D:4D ratios. Postnatal treatment with flutamide, DHT, or estradiol did not affect digit ratio. The 2D:4D ratio could be feminized in male embryos by antagonizing AR activity and masculinized in female embryos by opposing ER activity with the ER antagonist fulvestrant. The 2D:4D ratio was determined by the length of 4D, and cell proliferation in 4D was increased by pharmacological manipulations that increased AR activity and decreased by those that increased ER activity. Antagonism of AR in male mice and of ER in female mice resulted in differential expression of mRNAs encoding various proteins involved in skeletal development. Thus, the sexual dimorphism in 2D:4D ratios results from the relative difference between androgen and estrogen signaling in the developing limb bud of 4D.

Z. Zheng, M. J. Cohn, Developmental basis of sexually dimorphic digit ratios. Proc. Natl. Acad. Sci. U.S.A. 108, 16289–16294 (2011). [Abstract] [Full Text]

J. T. Manning, Resolving the role of prenatal sex steroids in the development of digit ratio. Proc. Natl. Acad. Sci. U.S.A. 108, 16143–16144 (2011). [Full Text]