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Arkhat Abzhanov
Harvard Medical School
Department of Genetics
77 Avenue Louis Pasteur
Boston, MA
02115

(617) 432-6534

aabzhano@genetics.med.harvard.edu


Craniofacial development and evolution

(NOTE: I am currently in the process of setting up my own laboratory at the Harvard School of Dental Medicine, Oral Developmental Biology Department)

EVOLUTION. The faces of vertebrates are often readily recognizable as they display a number of species-specific characteristics. The beaks of birds in addition to the ordinary feeding function also serve as important tools and display stunning adaptive variation. Darwin’s Finches are a classic example of species multiplication and diversification caused by natural selection. The 14 species display impressive variation in beak morphology that is associated with the exploitation of a variety of ecological niches but whose developmental basis is unknown. We have discovered that one way in which beak morphology is developmentally regulated, and that morphological differences among species can be observed as early as the fifth day of development. We performed a comparative analysis of expression patterns of various growth factors during craniofacial development in six species of Ground Finches comprising the genus Geospiza. We found that level and timing of expression of Bone morphogenic factor 4 (Bmp4) in the distal mesenchyme of the upper beaks strongly correlated with broader and deeper beaks characteristic of the seed-eating Ground Finches. When misexpressed in chick frontonasal primordium, Bmp4 caused a significant increase in the upper beak depth and height, paralleling the beak morphology of the Large Ground Finch. In my own lab I will continue to focus on the molecular nature of the evolutionary changes in Darwin’s Finches.

NEURAL CREST DIFFERENTIATION. During development neural crest cells give rise to a wide variety of specialized cell types in response to cytokines from surrounding tissues. Depending on the cranial-caudal level of their origin, different populations of neural crest cells exhibit differential competence to respond to these signals as exemplified by the unique ability of cranial neural crest to form skeletal cell types. We showed that in addition to differences whether they respond to particular signals, cranial neural crest cells differ dramatically from the trunk neural crest cells in how they respond to specific extracellular signals, such that under identical conditions the same signal induces dissimilar cell fate decisions in the two populations in vitro. Conversely, the same differentiated cell types are induced by different signals in the two populations. These in vitro differences in neural crest response are consistent with in vivo manipulations. We also provided evidence that these differences in responsiveness are modulated, at least in part, by differential expression of Hox genes within the neural crest. In the future, I will continue investigations into the mechanisms of cranial neural crest differentiation into skeletal and other cell types.

EARLY CRANIOFACIAL PATTERNING. Recent molecular and fate mapping studies have shown that an important signaling organizer exists in the frontonasal primordium of a developing chick embryo that is defined by juxtaposition of the Sonic hedgehog and Fibroblast growth factor 8 expression domains. This molecular expression interface presages any detectable growth of the frontonasal primordium and experiments involving transplantation of the epithelium containing the boundary demonstrated it to be a source of dorsal-ventral and rostral-caudal patterning information for the neural crest-derived mesenchyme of the upper beak. We directly addressed the possibility that Shh and Fgf8 regulate each other in the surface ectoderm of the frontonasal process. Experiments involving either blocking or ectopically activating Shh and Fgf8 activities revealed mutual antagonism between the two genes in the epithelium at the relevant developmental stages. We proposed that such Shh and Fgf8 interactions are important for the establishment and maintenance of the molecular boundary patterning the face. Similar experiments will be carried out in the future to further elaborate the molecular interactions during facial patterning.

BEAK MORPHOGENESIS. Much of the skeleton and connective tissue of the vertebrate head is derived from cranial neural crest. During development, cranial neural crest cells migrate from the dorsal neural tube to populate the forming face and pharyngeal arches. Fgf8 and Shh, signaling molecules known to be important for craniofacial development, are expressed in distinct domains in the developing face. Specifically, in chick embryos these molecules are expressed in adjacent but non-overlapping patterns in the epithelium covering crest-derived mesenchyme that will give rise to the skeletal projections of the upper and lower beaks. It has been suggested that these molecules play important roles in patterning the developing face. We directly examine the ability of FGF8 and SHH signaling, singly and in combination, could to regulate cranial skeletogenesis, both in vitro and in vivo. We find that SHH and FGF8 have strong synergistic effects on chondrogenesis in vitro and are sufficient to promote outgrowth and chondrogenesis in vivo, suggesting a very specific role for these molecules in producing the elongated beak structures during chick facial development.

DERMAL BONE DEVELOPMENT. Development of the vertebrate skeleton depends on a multitude of genes regulating patterning and growth of cells within mesenchymal condensations that later develop into skeletal elements. In the trunk, these condensations form from somatic sclerotomes and lateral plate mesoderm and give rise to the axial and limb skeletal structures, respectively, through a process of endochondral ossification, where cartilage templates form first and are later replaced with bone. In contrast, the vertebrate skull arises from two distinct lineages of skeletogenic mesenchyme: paraxial mesoderm and neural crest. The paraxial mesoderm contribution is limited to the posterior-most cartilages and bones of the skull. Most bones and cartilages of the head, including skull cranial vault, jaws and face form neural crest. In addition to forming cartilages and endochondral bones, cranial skeletogenic tissues, both mesoderm and neural crest, produce intramembranous (dermal) bone, which forms directly through ossification in the cranial dermis. While chondrogenesis and endochondral ossification are relatively well studied, the intramembranous (dermal) bone development is very poorly understood. My goal is to analyze formation of cranial intramembranous (dermal) bone on both cellular and tissue levels. More specifically, we are interested in roles of two important growth factors, Bone Morphogenic Proteins 2 and 4 (BMP2 and BMP4), in intramembranous (dermal) bone development. This will continue to be one of the major projects in my laboratory.

PUBLICATIONS:

1. Abzhanov, A., Meredith Protas, B. Rosemary Grant, Peter R. Grant, Clifford J. Tabin (2004). Bmp4 and Morphological Variation of Beaks in Darwin's Finches. Science, 305, 1462.

2. Abzhanov, A., and Tabin,C.J. (2004). Shh and Fgf8 act synergistically to drive cartilage outgrowth during cranial development. Dev Biol. 273, 134.

3. Abzhanov, A., Tzahor, E., Lassar, A.B. and Tabin, C.J. (2003) Dissimilar Regulation of Cell Differentiation in Mesencephalic (Cranial) and sacral (Trunk) Neural Crest Cells. Development 130, 4567.

4. Tzahor, E., Kempf, H., Mootoosamy, R., Poon, A., Abzhanov, A, Tabin, C.J., Dietrich, S. and Lassar, A. (2003) Antagonists of Wnt and BMP signaling induce the formation of vertebrate head muscle. Genes and Development 17, 3087.

5. Abzhanov, A., and Kaufman, T.C. (2003) HOX Genes and Tagmatization of the Higher Crustacea (Malacostraca), In: Evolutionary Developmental Biology of Crustacea ( ed. Gerhard Scholtz), Balkema Publishers, Lisse

6. Abzhanov, A., Holtzman, S., and Kaufman, T.C. (2001) The Drosophila proboscis is specified by two Hox genes, proboscipedia and Sex combs reduced, via repression of leg and antennal appendage genes. Development 128, 2803.

7. Abzhanov, A., and Kaufman, T.C. (2000) Crustacean (Malacostracan) Hox genes and the evolution of the arthropod trunk. Development 127, 2239.

8. Abzhanov, A., and Kaufman, T.C. (2000) Evolution of distinct expression patterns for engrailed paralogues in higher crustaceans (Malacostraca). Development Genes and Evolution 210, 493.

9. Abzhanov, A., and Kaufman, T.C. (2000) Embryonic expression patterns of the Hox genes of the crayfish Procambarus clarkii (Decapoda, Crustacea). Evolution and Development 5, 271.

10. Abzhanov, A., and Kaufman, T.C. (2000) Homologs of Drosophila appendage genes in patterning of arthropod limbs. Developmental Biology 227, 673.

11. Abzhanov, A. and Kaufman, T.C. (1999). Novel regulation of the homeotic gene Scr associated with a crustacean leg-to-maxilliped appendage transformation. Development 126, 1121.

12. Abzhanov, A., Popadic, A., and Kaufman, T.C. (1999). Chelicerate Hox genes and the homology of arthropod segments. Evolution and Development 2, 77.

13. Abzhanov, A. and Kaufman, T.C. (1999). Homeotic genes and the mandibulate head: divergent expression patterns of labial, proboscipedia and Deformed homologues in crustaceans and insects. Proc. Natl. Acad. Sci. 96 (18), 10224.

14. Popadic, A., Abzhanov, A., Rousch, D., and Kaufman, T.C. (1998). Understanding the genetic basis of morphological evolution: the role of homeotic genes in the diversification of the arthropod bauplan. International Journal of Developmental Biology 42, 453.