Brain Face

**Abstract(s):** **(1) Short-faced mice and developmental interactions between the brain and the face:** The length of the face represents an important axis of variation in mammals and especially in primates. Mice with mutations that produce variation along this axis present an opportunity to study the developmental factors that may underlie evolutionary change in facial length. The Crf4 mutant, obtained from the C57BL/6J (wt/wt) background by chemical mutagenesis by the Baylor Mouse Mutagenesis Resource, is reported to have a short-faced phenotype. As an initial step towards developing this model, Boughner et al. (2008) performed 3D geometric morphometric comparisons of Crf4 mice to C57BL/6J wild-type mice focusing on three stages of face development and morphology – embryonic (E10.5–11.5), neonatal, and adult. Morphometric analysis of adult Crf4 mutants revealed that in addition to a shortened face, these mice exhibit a significant reduction in brain size and basicranial length. These same features also differ at the neonatal stage. During embryonic face formation, only dimensions related to brain growth were smaller, whereas the Crf4 face actually appeared advanced relative to the wild-type at the same somite stage. These results show that aspects of the Crf4 phenotype are evident as early as embryonic face formation. Based on their anatomical findings, the authors hypothesize that the reduction in facial growth in Crf4 mice is a secondary consequence of reduction in the growth of the brain. If correct, the Crf4 mutant will be a useful model for studying the role of epigenetic interactions between the brain and face in the evolutionary developmental biology of the mammalian craniofacial complex as well as human craniofacial dysmorphology. **(2) Epigenetic integration of the developing brain and face:** The integration of the brain and face and to what extent this relationship constrains or enables evolutionary change in the craniofacial complex is an issue of long-standing interest in vertebrate evolution. To investigate brain-face integration, Parsons et al. (2011) studied the covariation between the forebrain and midface at gestational days 10–10.5 in four strains of laboratory mice. The authors found that phenotypic variation in the forebrain is highly correlated with that of the face during face formation such that variation in the size of the forebrain correlates with the degree of prognathism and orientation of the facial prominences. This suggests strongly that the integration of the brain and face is relevant to the etiology of midfacial malformations such as orofacial clefts. This axis of integration also has important implications for the evolutionary developmental biology of the mammalian craniofacial complex. **(3) Epigenetic interactions and the structure of phenotypic variation in the cranium:** Understanding the developmental and genetic basis for evolutionarily significant morphological variation in complex phenotypes such as the mammalian skull is a challenge because of the sheer complexity of the factors involved. Hallgrimsson et al. (2007) hypothesize that even in this complex system, the expression of phenotypic variation is structured by the interaction of a few key developmental processes. To test this hypothesis, the authors created a highly variable sample of crania using four mouse mutants and their wild-type controls from similar genetic backgrounds with developmental perturbations to particular cranial regions. Using geometric morphometric methods, Hallgrimsson and colleagues compared patterns of size, shape, and integration in the sample within and between the basicranium, neurocranium, and face. The results highlight regular and predictable patterns of covariation among regions of the skull that presumably reflect the epigenetic influences of the genetic perturbations in the sample. Covariation between relative widths of adjoining regions is the most dominant factor, but there are other significant axes of covariation such as the relationship between neurocranial size and basicranial flexion. Although there are other sources of variation related to developmental perturbations not analyzed in this study, the patterns of covariation created by the epigenetic interactions evident in this sample may underlie larger scale evolutionary patterns in mammalian craniofacial form. **(4) Mechanisms that underlie co-variation of the brain and face:** The effect of the brain on the morphology of the face has long been recognized in both evolutionary biology and clinical medicine. In this work, Marcucio et al. (2011) describe factors that are active between the development of the brain and face and how these might impact craniofacial variation. First, there is the physical influence of the brain, which contributes to overall growth and morphology of the face through direct structural interactions. Second, there is the molecular influence of the brain, which signals to facial tissues to establish signaling centers that regulate patterned growth. Importantly, subtle alterations to these physical or molecular interactions may contribute to both normal and abnormal variation. These interactions are therefore critical to our understanding of how a diversity of facial morphologies can be generated both within species and across evolutionary time.