To elucidate the functional role of the Dlx3 homeodomain protein during early development and epidermal differentiation, we are currently in the process of determining the target genes and the Dlx3 interacting factors necessary to exert the transcription regulatory function. Identification of Dlx3 interacting proteins is being performed by affinity chromatography followed by mass spectrometry. Initial studies of transduced cells showed a delayed growth when compared to untransduced cells. A detectable difference in morphology was also noted among the cell lines. Furthermore, biochemical characterization of a mutant form of Dlx3 that in humans is associated with the autosomal dominant Tricho-Dento-Osseous (TDO) syndrome is also being performed. TDO syndrome is characterized by defects in ectodermal derivatives such as hair and teeth and craniofacial bone abnormalities. Recent findings show that Dlx3 is also expressed in the developing bone, and the expression is retained in trabecular bone of the adult skeleton.? Stratification of the epidermis commences during embryonic development and is a process that continues to occur throughout the life of the organism. The process entails the outward movement of the proliferative basal cells that are adjacent to the basement membrane toward the surface of the skin. The stratification is concurrent with a Ca++-dependent differentiation process and the layer-specific expression of structural and enzymatic markers, with the basal proliferative cell differentiating first to a spinous cell, then to a granular cell, to ultimately terminally differentiate as a cornified, anucleated cell. A central role in the transduction of Ca++ signals is played by members of the EF-hand containing Ca++-binding proteins. The functionality of the EF-hand motifs may contribute to specificity in the interaction with the target molecules. Thus, it is through the binding of Ca++ by the EF-motifs that these proteins are able to bind or liberate target interacting proteins and in this way modulate their functions. We have identified novel Ca++-binding proteins, which we have termed Scarf and Scarf2, which have homology to Calmodulin. Identification of Scarf target proteins is being performed by immunoprecipitation assays followed by mass spectrometry.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Arthritis, Musculoskeletal, Skin Dis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hwang, Joonsung; Kalinin, Alexandr; Hwang, Meeyul et al. (2007) Role of Scarf and its binding target proteins in epidermal calcium homeostasis. J Biol Chem 282:18645-53
Radoja, Nadezda; Guerrini, Luisa; Lo Iacono, Nadia et al. (2007) Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias. Development 134:13-8
Hassan, Mohammad Q; Tare, Rahul S; Lee, Suk Hee et al. (2006) BMP2 commitment to the osteogenic lineage involves activation of Runx2 by DLX3 and a homeodomain transcriptional network. J Biol Chem 281:40515-26
Mukhopadhyay, Mahua; Gorivodsky, Marat; Shtrom, Svetlana et al. (2006) Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium. Development 133:2149-54
Depew, Michael J; Simpson, Carol A; Morasso, Maria et al. (2005) Reassessing the Dlx code: the genetic regulation of branchial arch skeletal pattern and development. J Anat 207:501-61
Morasso, Maria I; Radoja, Nadezda (2005) Dlx genes, p63, and ectodermal dysplasias. Birth Defects Res C Embryo Today 75:163-71
Hwang, M; Kalinin, A; Morasso, M I (2005) The temporal and spatial expression of the novel Ca++-binding proteins, Scarf and Scarf2, during development and epidermal differentiation. Gene Expr Patterns 5:801-8
Morasso, Maria I; Tomic-Canic, Marjana (2005) Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell 97:173-83
Berghorn, K A; Clark, P A; Encarnacion, B et al. (2005) Developmental expression of the homeobox protein Distal-less 3 and its relationship to progesterone production in mouse placenta. J Endocrinol 186:315-23
Hassan, Mohammad Q; Javed, Amjad; Morasso, Maria I et al. (2004) Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene. Mol Cell Biol 24:9248-61

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