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Research
Developmental Skin Biology Unit
Maria I. Morasso, Ph.D.
Unit Leader, Developmental Skin Biology Unit
Phone: (301) 402-2888
Fax: (301) 435-7910
E-mail: morassom@mail.nih.gov
Role of homeobox transcription factors in the regulation of differentiation
Our research has focused in characterizing the regulation and function of Dlx3 homeobox transcription factor, a member of the murine Dlx family, with essential roles in epidermal, osteogenic and placental development. Dlx3 is specifically expressed in developing ectodermal appendages (hair, teeth, nail) as well as in developing bone (craniofacial and appendicular). The importance of Dlx3 in the patterning and development of ectodermal structures derived from epithelial-mesenchymal interactions during embryogenesis (i.e. tooth, hair) is corroborated by the effects of DLX3 mutations in patients with the autosomal dominant Tricho-Dento-Osseous (TDO) syndrome. Anomalies in epithelial/mesenchymal-derived organs are characteristics of a group of about 150 human heritable pathological disorders defined as ectodermal dysplasias (EDs). DLX3 is among the few genes for which mutations have been directly linked with EDs.
Our current work on the epidermal-conditional ablation of Dlx3 has determined the crucial role of this homeodomain transcription factor in epidermal stratification and hair development. Although Dlx3 has been implicated in skeletal development in the human autosomal dominant TDO syndrome, where the mutation is associated with defects in the intramembranous and endochondral bone (increased bone density), a direct role for Dlx3 in bone formation has not been identified. Up to now, our collaborative work has accumulated ex vivo evidence showing that Dlx3 induction coincides with the onset of commitment to osteogenic lineage, and that key markers of bone differentiation are regulated by Dlx3. Future projects will involve the analysis of mouse models (KO, Kin and transgenic) established in the laboratory to further elucidate the role of Dlx3 in bone formation and homeostasis. We are also performing analysis of conditional knockout lines to elucidate the signaling and regulatory pathways requiring normal Dlx3 function during embryogenesis.
Identification and characterization of novel epidermal- and differentiation-specific genes
Performing a Suppressive Subtractive Hybridization (SSH) screen we identified 2 novel epidermal differentiation-specific transcripts we termed Scarf and Suprabasin. The Scarf ORF has homology to Calmodulin-like proteins and encodes a protein that contains four conserved EF-hand motifs, putative Ca++-binding domains. The Ca++ signaling dependent systems, such as the keratinocyte differentiation process are tuned for effective response to transient variations in Ca++ concentration. A central role in the transduction of Ca++ signals is played by members of the Ca++-binding proteins. 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. Scarf has restricted differential expression in the suprabasal layers of the epidermis and utilizing immunoprecipitation assays followed by mass spectrometry, we have identified Scarf target proteins to elucidate the function of Scarf in the overall program of skin differentiation.
During embryonic mouse development, Suprabasin mRNA was detected at day 15.5, coinciding with epidermal stratification. Suprabasin was detected in the suprabasal layers of the epithelia in the tongue, stomach and epidermis. The 2.2 Kb cDNA transcript encodes a protein of 72 kDa with a predicted PI of 6.85. The translated sequence has an amino terminal domain, a central domain composed of repeats rich in glycine and alanine, and a carboxy terminal domain. Cross-linking experiments indicate that Suprabasin is a substrate for TGase2 and TGase3 activity. Altogether, these results indicate that the Suprabasin protein potentially plays a role in the process of epidermal differentiation.
| Dlx3 expression in the hair matrix cells of the hair follicle at
postnatal day 1 (P1) Dlx3Kin skin. Anti-beta-galactosidase antibody (red), co-stained with anti-K14 antibody (Green) and DAPI (Blue).) |
Selected Publications
LoIacono, N., Chiarelli, A., Mantero, S., Garcia, E., Mills, A.A., Morasso, M.I., Costanzo, A., Levi, G., Guerrini, L. and Merlo, G. (2008) p63 regulates expression of Dlx genes in the embryonic limbs: a transcription regulation at the basis of limb congenital defects in EEC and SHFM. Development 135, 1377-1388.
Hwang, J., Mehrani, T., Millar, S.E. and Morasso, M.I. (2008) Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Development. In Press.
Duverger, O., Lee D., Hassan M.Q., Chen S.X., Jaisser F., Lian J.B., Morasso, M.I. (2008) Molecular consequences of a frameshifted Dlx3 mutant leading to Tricho-Dento-Osseous. J. Biol. Chem. 283, 20198-20208.
Radoja, N, Guerrini, L., LoIacono, N., Merlo, G.R., Constanzo, A., Weinberg, W., LaMantia, G., Calabro, V., Morasso, M.I. Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias. Development. 2007; 134, 13-18.
Hwang, J., Hwang, M., Kalinin, A., Anderson, D.E., Stojadinovic, O., Tomic-Canic, M., Kim, M. J., Lee, S. and Morasso, M.I. (2007) Role of Scarf and its target proteins in epidermal calcium homeostasis. J. Biol. Chem. 282, 18645-18663.
See complete list of publications
Updated July 24, 2008
