Organisms represent a complex arrangement of anatomical structures and individuated parts that must maintain functional associations through development. This integration of variation between functionally related body parts and the modular organization of development are fundamental determinants of their evolvability. This is because integration results in the expression of coordinated variation that can create preferred directions for evolutionary change, while modularity enables variation in a group of traits or regions to accumulate without deleterious effects on other aspects of the organism. Using our own work on both model systems (e.g., lab mice, avians) and natural populations of rodents and primates, we explore in this paper the relationship between patterns of phenotypic covariation and the developmental determinants of integration that those patterns are assumed to reflect. We show that integration cannot be reliably studied through phenotypic covariance patterns alone and argue that the relationship between phenotypic covariation and integration is obscured in two ways. One is the superimposition of multiple determinants of covariance in complex systems and the other is the dependence of covariation structure on variances in covariance-generating processes. As a consequence, we argue that the direct study of the developmental determinants of integration in model systems is necessary to fully interpret patterns of covariation in natural populations, to link covariation patterns to the processes that generate them, and to understand their significance for evolutionary explanation.

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The biology of bone healing is a rapidly developing science. Advances in transgenic and gene-targeted mice have enabled tissue and cell-specific investigations of skeletal regeneration. As an example, only recently has it been recognized that chondrocytes convert to osteoblasts during healing bone, and only several years prior, seminal publications reported definitively that the primary tissues contributing bone forming cells during regeneration were the periosteum and endosteum. While genetically modified animals offer incredible insights into the temporal and spatial importance of various gene products, the complexity and rapidity of healing— coupled with the heterogeneity of animal models—renders studies of regenerative biology challenging. Herein, cells that play a key role in bone healing will be reviewed and extracellular mediators regulating their behavior discussed. We will focus on recent studies that explore novel roles of inflammation in bone healing, and the origins and fates of various cells in the fracture environment.

A fundamental set of patterning genes may define the global organization of the craniofacial region. One of our goals has been to identify these basic patterning genes and understand how they regulate outgrowth of the frontonasal process, which gives rise to the mid and upper face. We identified a molecular boundary in the frontonasal process ectoderm, defined by the juxtaposed domains of Fibroblast growth factor 8 and Sonic hedgehog, which presaged the initial site of frontonasal process outgrowth. Fate maps confirmed that this boundary region later demarcated the dorsoventral axis of the upper beak. Ectopic transplantation of the ectodermal boundary region activated a cascade of molecular events that reprogrammed the developmental fate of neural crest-derived mesenchyme, which resulted in duplications of upper and lower beak structures. We discuss these data in the context of boundary/morphogen models of patterning, and in view of the recent controversy regarding neural crest prepatterning versus neural crest plasticity.

From an architectural point of view, the forebrain acts as a framework upon which the middle and upper face develops and grows. In addition to serving a structural role, we present evidence that the forebrain is a source of signals that shape the facial skeleton. In this study, we inhibited Sonic hedgehog (Shh) signaling from the neuroectoderm then examined the molecular changes and the skeletal alterations resulting from the treatment. One of the first changes we noted was that the dorsoventral polarity of the forebrain was disturbed, which manifested as a loss of Shh in the ventral telencephalon, a reduction in expression of the ventral markers Nkx2.1 and Dlx2, and a concomitant expansion of the dorsal marker Pax6. In addition to changes in the forebrain neuroectoderm, we observed altered gene expression patterns in the facial ectoderm. For example, Shh was not induced in the frontonasal ectoderm, and Ptc and Gli1 were reduced in both the ectoderm and adjacent mesenchyme. As a consequence, a signaling center in the frontonasal prominence was disrupted and the prominence failed to undergo proximodistal and mediolateral expansion. After 15 days of development, the upper beaks of the treated embryos were truncated, and the skeletal elements were located in more medial and proximal locations in relation to the skeletal elements of the lower jaw elements. These data indicate that a role of Shh in the forebrain is to regulate Shh expression in the face, and that together, these Shh domains mediate patterning within the frontonasal prominence and proximodistal outgrowth of the middle and upper face.