A chick leg can be coaxed into growing five mammalian-like digits instead of its usual four, opening a window onto 350 million years of limb evolution. This matters because scientists disagree on how embryos use signalling molecules to sculpt digits. In chicks, Sonic hedgehog (Shh) acts as a classic morphogen, forming a concentration gradient that tells cells where to build each digit. In mice, Shh works differently, through unknown secondary signals. The new chick model with five digits—a mammalian trait—lets researchers compare the two systems directly, testing whether a shared Shh-Bmp2-p27Kip1 pathway explains why birds and mammals evolved different numbers of digits. If the project succeeds, it will unify these conflicting models into a single framework for how amniotes pattern their limbs. That framework is fundamental science: it deepens understanding of the rules that shape anatomy, with no immediate practical application. But similar fundamental work on developmental signalling has previously illuminated the origins of congenital limb malformations, and a clearer picture of digit specification could eventually inform tissue engineering or regenerative approaches to birth defects.
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Positional information is a fundamental principle in embryonic development. It describes how cells interpret the concentration of signalling molecules to acquire positional values, which are then interpreted into distinct morphological outcomes. In the classic model, a Sonic hedgehog (Shh) signalling gradient specifies the positional values of the three chick wing digits and four chick leg digits by acting as a morphogen. However, recent work on the mouse limb with five digits suggests that Shh does not act as a morphogen, but instead acts through undefined secondary signalling molecules. In this proposal, we will build upon two major recent advances from our lab: 1) The development of a mammalian-like pentadactyl chick leg model: The chick leg has a phalangeal count in its four digits that has remained stable for over 350 million years. We have developed a chick leg model with five digits that has a mammalian phalangeal count, which can give insights into the underlying mechanisms that caused evolutionary changes in amniote digit patterning. 2) The discovery of a Shh-Bmp2-p27Kip1 pathway in the chick wing: This pathway plays a key role in specifying the identity of digit 3 and inhibiting posterior digit formation, potentially explaining key differences between mammalian and avian digit patterning. We will characterise the digits of the pentadactyl chick leg model to understand how closely they resemble mammalian digit identities. To do this, we will compare the transcriptomic profiles of the digits in normal and mammalianised chick legs with those of mouse hindlimbs, focussing on transcription factors and signalling proteins potentially involved in determining digit identity. We will investigate the involvement of the Shh-Bmp2-p27kip1 pathway in determining digit number in the chick leg and explore whether different Bmp proteins specify its distinct digit identities. We will also determine if this pathway is expressed in the mouse limb to understand if its activity could be responsible for the evolutionary differences between avian and mammalian limbs. The implications of this research extend beyond basic developmental biology. They could offer new insights into limb malformations and birth defects, with potential applications in regenerative medicine and tissue engineering. By unifying different models of digit patterning, this project aims to bridge gaps in evolutionary biology and provide a comprehensive framework for understanding digit reduction and diversification among amniotes. This work aligns closely with the BBSRC Strategic Delivery Plan 2022-2025, particularly its aim of "Understanding the Rules of Life." By investigating how positional information influences digit patterning, we will contribute to a deeper understanding of the fundamental mechanisms that shape anatomy.
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