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PNAS 108 (39): 16289-16294

Copyright © 2011 by the National Academy of Sciences.

From the Cover


Developmental basis of sexually dimorphic digit ratios

Zhengui Zheng Martin J. Cohn1

Howard Hughes Medical Institute and Department of Molecular Genetics and Microbiology and Department of Biology, University of Florida, Gainesville, FL 32610

Edited by David M. Kingsley, Stanford University, Stanford, CA, and approved August 3, 2011 (received for review June 7, 2011)

Abstract: Males and females generally have different finger proportions. In males, digit 2 is shorter than digit 4, but in females digit 2 is the same length or longer than digit 4. The second- to fourth-digit (2D:4D) ratio correlates with numerous sexually dimorphic behavioral and physiological conditions. Although correlational studies suggest that digit ratios reflect prenatal exposure to androgen, the developmental mechanism underlying sexually dimorphic digit development remains unknown. Here we report that the 2D:4D ratio in mice is controlled by the balance of androgen to estrogen signaling during a narrow window of digit development. Androgen receptor (AR) and estrogen receptor α (ER-α) activity is higher in digit 4 than in digit 2. Inactivation of AR decreases growth of digit 4, which causes a higher 2D:4D ratio, whereas inactivation of ER-α increases growth of digit 4, which leads to a lower 2D:4D ratio. We also show that addition of androgen has the same effect as inactivation of ER and that addition of estrogen mimics the reduction of AR. Androgen and estrogen differentially regulate the network of genes that controls chondrocyte proliferation, leading to differential growth of digit 4 in males and females. These studies identify previously undescribed molecular dimorphisms between male and female limb buds and provide experimental evidence that the digit ratio is a lifelong signature of prenatal hormonal exposure. Our results also suggest that the 2D:4D ratio can serve as an indicator of disrupted endocrine signaling during early development, which may aid in the identification of fetal origins of adult diseases.

Key Words: limb development • sexual dimorphism • steroid hormones

Author contributions: Z.Z. and M.J.C. designed research; Z.Z. performed research; Z.Z. and M.J.C. analyzed data; and Z.Z. and M.J.C. wrote the paper.

The authors declare no conflict of interest.

See Commentary on page 16143.

This article is a PNAS Direct Submission.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: mjcohn{at}

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