Temperature regulates limb length in homeotherms by directly modulating cartilage growth.

Allen's Rule documents a century-old biological observation that strong positive correlations exist among latitude, ambient temperature, and limb length in mammals. Although genetic selection for thermoregulatory adaptation is frequently presumed to be the primary basis of this phenomenon, important but frequently overlooked research has shown that appendage outgrowth is also markedly influenced by environmental temperature. Alteration of limb blood flow via vasoconstriction/vasodilation is the current default hypothesis for this growth plasticity, but here we show that tissue perfusion does not fully account for differences in extremity elongation in mice. We show that peripheral tissue temperature closely reflects housing temperature in vivo, and we demonstrate that chondrocyte proliferation and extracellular matrix volume strongly correlate with tissue temperature in metatarsals cultured without vasculature in vitro. Taken together, these data suggest that vasomotor changes likely modulate extremity growth indirectly, via their effects on appendage temperature, rather than vascular nutrient delivery. When combined with classic evolutionary theory, especially genetic assimilation, these results provide a potentially comprehensive explanation of Allen's Rule, and may substantially impact our understanding of phenotypic variation in living and extinct mammals, including humans.