November 11, 2009
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JAX Scientists Facilitate Craniofacial Development Research

If you aren't quite sure how the human face is formed, you're not alone. Biologists have long been mystified by how bud-like colonies of embryonic cells form near the primitive mouth in early pregnancy, communicate with nearby tissues, and orchestrate the development and organization of bone, cartilage, ligament, nerve, and soft tissues into a human head and face. Unfortunately, scientists also don't know what sometimes goes wrong and causes facial defects like cleft lip and palate. Perhaps some of the answers will be found as a result of 11 research and technology grants issued by the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health. The grants are part of the NIDCR's "FaceBase Consortium", a five-year initiative that hopes to identify and define the genes involved in constructing the human mid-face, which includes the nose, upper lip, and palate. Eventually, FaceBase's focus may expand to tooth, salivary gland, and other craniofacial tissue development.

Facebase at JAX

Historically, the mechanisms that orchestrate the formation of the human head and face have been investigated in the relative isolation of individual research labs. FaceBase was designed to break that isolation and bring researchers together. In that spirit, the FaceBase Consortium grants were awarded to 14 principal investigators who specialize in certain aspects of craniofacial development. Among those specialists are Drs. Leah Rae Donahue and Stephen Murray of The Jackson Laboratory's Genetic Tools and Resources for Orofacial Clefting Research project. Dr. Donahue is a Senior Research Scientist and Director of JAX's Genetic Resources. One of her laboratory's goals is to identify and characterize reliable genetic and physiological mouse models for human craniofacial disorders and to share these and other models for human skeletal diseases with the scientific public. Dr. Murray began his career at JAX as a postdoctoral fellow with Dr. Tom Gridley. He investigated the role of different genes in the development of the secondary palate using Cre-lox technology, a genetic tool that allows target genes to be deleted in specific cell types at specific times. Now, as a Research Scientist in Genetic Resource Science, Dr. Murray is interested in expanding and improving the toolbox of Cre strains available to the scientific community. Through the JAX FaceBase project, Drs. Murray and Donahue will generate and distribute 15 new Cre driver strains to facilitate orofacial clefting research. Additionally, JAX will serve as a repository for existing and future tools and models of cleft lip and palate. Says Dr. Murray: "This project will have an important impact on orofacial clefting research by increasing the number of tool and model strains available to investigators around the world. We also hope it will serve as a model for the development of mouse genetic resources in other disease areas."

Donahue Murray
Through the FaceBase Project, Drs. Leah Rae Donahue and Stephen Murray will generate and distribute 15 new Cre driver strains to facilitate orofacial clefting research.

FaceBase Database

An essential aspect of the FaceBase Consortium will be the FaceBase Database, a free and publicly accessible database that will help craniofacial researchers accelerate their research. The database will house and cross-link data from biochemical, molecular, genetic, and imaging studies conducted in zebrafish, mice, and other organisms. FaceBase organizers hope to have a prototype ready within the next year and a fully functioning database soon thereafter.

The end result of the FaceBase Consortium will be well worth the effort. Says Steven Scholnick, Ph.D., an NIDCR scientist who administers the FaceBase initiative: "If you sketch out the whole consortium on paper, you can easily see how the projects are mutually reinforcing and how interconnecting all of these diverse sets of data can be useful to the entire craniofacial research community – individual labs won't have to each invent their own part of the wheel and can instead focus on the bigger, systems-level picture. It's even more exciting to think that this consortium can lead to collaborations we can't yet envision and that it could accelerate our efforts to help families with children born with craniofacial abnormalities."

The JAX Craniofacial Mutant Resource

The JAX Craniofacial Mutant Resource aims to discover and characterize new craniofacial mouse mutations and to provide the scientific community with models for facial, dental, eye, ear, and skull development research. New craniofacial deviants are identified from The Jackson Laboratory's twice-monthly deviant search. Before the mutants are included in the database, they are tested for heritability, characterized, and the chromosomal locations of the responsible mutant genes are mapped.

Selected JAX® Mice Strains From the Craniofacial Mutant Resource

Following are five of the many models available from the Craniofacial Mutant Resource. More detailed descriptions are available in the JAX® Mice Database, www.jax.org/jaxmice.

  • B6(NOD) H2g7-Sostdc1shk/J (005717) - harbors the spontaneous "sharkey" mutation, conferring an abnormal hard palate and extra upper and lower incisors with separate roots
  • STOCK Tg(KRT14-cre)1Amc/J (004782) - a Cre strain that can be used to generate tissue-specific targeted mutants for studying developmentally critical gene function in the ectoderm and its derivatives
  • STOCK Tg(KRT14-cre/Esr1)20Efu/J (005107) - a tamoxifen-inducible Cre strain that can be used to generate targeted keratinocyte-specific deletions
  • STOCK Tg(Wnt1-cre)11Rth Tg(Wnt1-GAL4)11Rth/J (003829) - a versatile strain that allows the simultaneous expression of Cre recombinase and GAL4 in the Wnt1 expression domain
  • B6;129S1-Osr2tm2(cre)Jian/J (009388) - Osr2-IresCre (or Osr2IresCre) mice may be used to generate conditional mutations for studying palate and kidney development (under development, submitted as part of the FaceBase program)

Reference

NIH News. 2009. NIDCR launches the FaceBase Consortium  http://www.nih.gov/news/health/oct2009/nidcr-05.htm. October 5, 2009.