Developmental atlas of murine face: Deciphering the evolutionary transition from reptilian jaw to mammalian nose

　The face is one of the most distinctive features of vertebrates, diverged widely among species while maintaining a highly complex anatomical structure. Notably, mammals have a “nose” that can actively sniff out smells, separate from the jaws, and this has increased the complexity of their faces compared to those of reptiles. How this mammalian face evolved has long been an overlooked mystery.

　In recent years, we have tackled this problem using mice, a key model in biomedical research. However, despite their importance in science, the detailed developmental process of mouse craniofacial structures remains poorly documented. This lack of data makes it difficult to compare mouse morphology with that of other vertebrates, including humans. To bridge this gap, Dr. Hiroki Higashiyama (RCIES, SOKENDAI, Japan) and his colleagues conducted a comprehensive three-dimensional analysis of mouse craniofacial development, shedding new light on the evolution of the mammalian and human face.

　Our study traced mouse facial development from mid embryonic stages (9.0 days post-coitum [dpc]) to just before birth (18.5 dpc). We used several staining methods to visualize the cartilages, bones, and nerves. Additionally, we reconstructed histological sections into 3D models, allowing us to examine the spatial relationships of skeletal, neural, and vascular structures. This data were summarized into hand-drawn illustrations for broader readers (Figure 1).

　The results showed that early head and peripheral nerve development in mice represent common patterns found in other jawed vertebrates. The early formation of the skull base cartilage also follows a typical mammalian pattern, and remains comparable to that of reptiles.

　Our findings challenge conventional views on upper jaw evolution. Traditionally, it was believed that mammalian jaw bones were directly inherited from reptiles. However, our results strongly support the Holo-maxillary hypothesis, which we previously proposed.

　This hypothesis suggests that during mammalian evolution, the premaxilla—an ancestral jawbone—was lost, and its region was repurposed to form the nose, separating it from the upper jaw. At the same time, a new jawbone, the incisivum emerged, incorporating elements from the septomaxilla and vomer. This implies that the mammalian upper jaw underwent a major structural reorganization, setting it apart from that of reptiles (Figure 2).By comparing our mouse data with human craniofacial development in the literature, we found that our proposed framework also applies to human facial morphology (Figure 3). In human fetal development, a temporary upper jawbone (incisivum) forms and later fuses with the maxilla, though reports on its ossification sites vary. Our hypothesis, which suggests that the incisivum consists of both septomaxillary and palatal elements, helps explain these discrepancies. This insight may also contribute to a better understanding of craniofacial disorders such as cleft lip and palate.

　The present study provides a detailed account of mouse craniofacial development, helping to reassess the evolutionary pathway of mammalian and human faces. Our research strengthens the foundation for biomedical studies using mice, and also addresses our fundamental question: How did our faces develop?