Integrative and Comparative Biology Advance Access originally published online on July 3, 2008
Integrative and Comparative Biology 2008 48(3):321-323; doi:10.1093/icb/icn068
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Building a better organismal model: The role of the mouse—Introduction to the symposium
*Department of Anatomy, New York College of Osteopathic Medicine, Old Westbury, NY 11568-8000, USA; Department of Biology, Mercer University, Macon, GA 31201, USA
Correspondence: 1E-mail: kcarlson{at}nyit.edu
"The literature is filled with statements about the mechanical function of this or that trait, or about the "superiority" of this or that design without a single experiment to back up the claim" (Lauder 1996
, p. 86).
One of the obstacles preventing a more in-depth understanding of the determinants of complex musculoskeletal traits has been a relative paucity of suitable organismal-level models for investigating their genesis. A complex trait, in this sense, is defined as having multiple contributing factors including behavioral, developmental, and environmental inputs, as well as interactions between any of these (Hofmann 2003). This symposium was organized around a central theme—demonstrating the unique capabilities of mouse models in investigating the manifestation of complex traits of the mammalian musculoskeletal system.
In comparison to choosing other animals for organismal-level models, selecting a house mouse has several distinct advantages. The small body size and relatively rapid maturation of mice encourages large samples and more cost-effective experimentation relative to most other animal models. A growing number of inbred strains exist (Vogel 2003; Wergedal et al. 2005), each of which essentially eliminates genetic variability from the list of factors contributing to the morphology or behavior in question. This provides an invaluable opportunity to investigate musculoskeletal responses in experimental designs (e.g., differences related to performance criteria) without introducing confounding genetic variability. Perhaps currently undervalued in importance, mice are behaviorally plastic (Crawley et al. 1997), which is a boon for functional morphologists studying masticatory and locomotor adaptations in the musculoskeletal system, or for conducting selection experiments to study evolutionary outcomes (Garland 2003). Continual advances in the field of genomics, particularly in the technology sector, have resulted in a more comprehensive understanding of the mouse genome, including the creation of new laboratory strains (Schughart and Churchill 2007). Relatedly, experimental manipulation of the mouse genome (e.g., knock-outs or transgenics) is an expanding area of research using mouse models (Austin et al. 2004). Thorough documentation of the mouse genome creates the possibility for tracing phenotypic responses (and differences therein) to precise genes through comparisons among inbred strains. This provides a powerful tool for studying evolutionary morphology (Cheverud et al. 1998).
Having briefly described why mouse models would be beneficial for functional morphologists, an eclectic series of investigations were assembled into a symposium in order to demonstrate how mouse models are beneficial in practice. The goal was to craft a program that featured a range of musculoskeletal adaptations, including both cranial and postcranial studies. Three of the contributions use a mouse model to address specific form–function relationships between the cranium/mandible and feeding adaptations. Byron et al. (2008) use a myostatin-deficient mouse model to investigate the role of presumed compressive forces (e.g., those generated during mastication) on the morphology of the temporal bone and squamosal suture. While they anticipated that more heavily muscled myostatin-deficient mice should have exhibited expanded temporal bones and more extensive overlap of adjoining cranial bones at the squamosal suture relative to wild-type controls, the opposite was observed. Myostatin-deficient mice exhibit less overlap of adjoining cranial bones at the squamosal suture relative to wild-type mice. Byron et al. suggest implications for interpreting cranial morphology of fossil hominins. Ravosa et al. (2008) also use a myostatin-deficient mouse model in order to assess the consequence of bite force on material properties (e.g., biomineralization) of the mandible and the articular cartilage of the temporomandibular joint (TMJ). They make parallel interspecific comparisons using rabbit models and mouse models, in which rabbits fed hard objects are analogous to greater bite forces in myostatin-deficient mice and rabbits fed soft objects are analogous to lesser bite forces in wild-type mice. The mandible of the myostatin-deficient mouse exhibits larger size-adjusted joint proportions and greater tissue density at the symphysis and TMJ relative to wild-type mice. Myostatin-deficient mice also exhibit compensatory effects (i.e., a suggested adaptive response) in the composition of the articular cartilage of the TMJ (i.e., greater viscoelastic properties as a result of elevated type-II collagen levels), unlike the rabbits fed hard objects, which, relative to rabbits fed soft objects, exhibit degradative effects in the articular cartilage (i.e., lower viscoelastic properties as a result of reduced type-II collagen levels). Ravosa et al. (2008) suggest that external dimensions alone may not adequately portray the adaptive plasticity of the jaw joint in extant or extinct taxa, which in turn may limit the accuracy of optimal design models that are based on strictly external dimensions. Vinyard and Payseur (2008) compare the genetic basis of maximum jaw-opening performance (i.e., gape) across 21 strains of inbred mice, then assess the heritability of several individual morphological characters that are known to affect gape. They find a strong heritable basis for maximum gape, but other than body size, no characters that are related to size of the masseter muscle or to the shape of the mandible consistently contribute to variability in jaw-opening performance across all strains. Vinyard and Payseur (2008) suggest that increasing maximum gape, while heritable itself, can be accomplished by several different configurational changes in these characters, which themselves also may be heritable.
Two contributions employ mouse models in the investigation of craniofacial development and patterns of cranial integration. Within the context of the spatial packing model (Biegert 1963), Hallgrimsson and Lieberman (2008) used three mutant-mouse models to discuss how developmental processes contribute to phenotypic covariation in the mouse craniofacial apparatus. They point out that inbred mouse models, by eliminating genetic variation, offer an opportunity to isolate the impact of specific genetic changes (e.g., mutations) or environmental effects on the covariation structure of a character, hence providing a means of testing its developmental determinants. In studies of evolutionary developmental biology, Hallgrimsson and Lieberman (2008) recommend that attention would be best directed towards key shared developmental processes that contribute to phenotypic covariation across broad phylogenetic boundaries (e.g., integration of brain size and morphology of the cranial base in mice and primates). Lopez et al. (2008) use a transgenic mouse model (i.e., overexpression of a truncated form of β-catenin in neuroprogenitor cells) to study the outcome of one particular developmental process (i.e., fetal encephalization) on phenotypic variation in morphology of the neurocranium and basicranium. They observed a larger neurocranium in newborn transgenic mice relative to genetically identical newborn wild-type mice, but no differences in body size, postcranial measurements, or length of the cranial base are observed between the two groups. This pattern of difference altered cranial base angle in the transgenic mice relative to that of wild-type mice. Lopez et al. (2008) suggest that prenatal encephalization tradeoffs may be restricted to cranial structures, as opposed to postcranial structures or to body size in general, but that change in many cranial structures likely results from the extent of integration of characters.
Two contributions apply mouse models in teasing apart the responses of the postcranial skeleton to altered conditions of loading associated with changes in activity levels or activity patterns. Middleton et al. (2008) update results of the long-term selective-breeding experiment of Garland et al. (Swallow et al. 1998; Garland 2003) for high levels of voluntary activity in mice (i.e., running in wheels). Middleton et al. note that onset of a previously reported postnatal reduction in the size of the triceps surae of "mini-muscle" mice relative to high-running and control groups (Garland et al. 2002) begins 
2 weeks after birth and results in a 50% reduction in adults. The cumulative reduction may be the result of nondifferentiation of type IIb muscle fibers in the "mini-muscle" mice. Middleton (2008) suggest that, among the various types of mouse models being used (e.g., inbred, transgenic, or knock-out), selection experiments provide a particularly naturalistic model for studying skeletal form, function, and evolution. Carlson et al. (2008) use an inbred mouse model to investigate trabecular architecture at the distal femoral metaphysis, and whether specific architectural adjustments (e.g., changes in bone volume fraction, degree of anisotropy) occur in response to specific alterations in activity patterns (e.g., linear versus nonlinear locomotion). Unlike an earlier study reporting an osseous response at the femoral midshaft in response to these different activity patterns (Carlson and Judex 2007), trabecular architecture at the distal femoral metaphysis of these same mice did not differ. Carlson et al. (2008) suggest that this indicates site specificity in the osteogenic response of femora, likely linked to localized differences between inferred loading regimes at these locations. They urged caution in making inferences about habitual locomotor behavior in animals on the basis of trabecular architecture.
In conclusion, this symposium demonstrates how mouse models (wild-type, inbred, transgenic, or knockout mice) can be adopted to experimentally address critical questions about the basis of morphological form. It is important, however, to temper this seemingly unlimited array of possibilities for comparative models by recognizing that laboratory mice have likely undergone divergent or artificial selection of their own (see Vinyard and Payseur 2008) and that the developmental genetic basis of morphological covariation in mice likely differs from that of other animals (see Hallgrimsson and Lieberman 2008). With such caveats in mind, we await and encourage the continued emergence of innovative applications of mouse models that answer the charge to experimentally investigate all facets of complexity in the mammalian musculoskeletal system, particularly with regards to evolutionary morphology.
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We would like to recognize the participants for their willing and eager involvement, as well as for their persistence. Without them, the symposium would have remained only an abstract idea. Thank you to each of you for your unique contributions, and please know that your continual encouragement for the symposium made a difference at many times along the way. We also wish to thank Chris Vinyard and the editor for sharing their comments during the writing of this introduction.
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From the symposium "Building a Better Organismal Model: The Role of the Mouse" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 2–6, 2008, at San Antonio, Texas.
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