Robert A. Schulz, Ph.D.

The goals of my research are to better understand genetic and molecular events controlling cell-fate specification and differentiation during development. Our experimental system is the laboratory fruit fly Drosophila, the best-studied animal in terms of developmental genetics. My laboratory has used this system to elucidate genetic hierarchies controlling body-wall muscle and heart development. An important contribution to the cardiogenesis field has been our discovery of genes that work combinatorially to control cardiac cell-fate determination during early heart development.

The regulation of cardiac gene expression by GATA zinc-finger transcription factors has been well documented in vertebrates. However, genetic studies in mice have failed to demonstrate a function for these proteins in cardiomyocyte specification. In Drosophila, the existence of a cardiogenic GATA factor was implicated through our detailed analysis of an enhancer for the D-mef2 myogenic differentiation gene. We have shown that the GATA gene pannier is expressed in the dorsal mesoderm, where it is required for cardiac cell formation. Ectopic expression of Pannier results in cardiac hyperplasia, while coexpression of Pannier and the homeodomain protein Tinman synergistically induce cardiac cell determination in both mesodermal and nonmesodermal cell types. The related GATA4 protein of mice likewise functions as a cardiogenic factor when expressed in the Drosophila heart. A gene-induction assay has additionally demonstrated an evolutionarily conserved function between Pannier and GATA4 in heart development. We have also documented a negative function for U-shaped, a member of the Friend of GATA class of proteins, in cardiac cell specification and demonstrated the existence of genetically distinct cardioblast subtypes in the Drosophila heart.

My research group is also taking advantage of the completion of the genome sequence of Drosophila and the extensive conservation of genes and signaling pathways between Drosophila and humans to identify genetic suppressors of the calcium-dependent phosphatase calcineurin. Our goal is to identify genes that are essential for calcineurin function in a physiologically relevant and genetically tractable system. Such studies should yield novel information on the genetic control of calcineurin-mediated signal transduction and may suggest new targets for the design of therapeutic drugs for potentially devastating heart and muscle diseases. Our results have so far been very encouraging in terms of the relevance of our biological assay and the efficacy of our genetic screen.

Recent publications

Wang J, Tao Y, Reim I, Gajewski K, Frasch M, Schulz RA (2005) Expression, regulation, and requirement of the Toll transmembrane protein during dorsal vessel formation in Drosophila melanogaster. Mol Cell Biol 25:4200–4210.
Sorrentino RP, Gajewski K, Schulz RA (2005) GATA factors in Drosophila heart and blood cell development. Semin Cell Dev Biol 16:107–116.
Schulz RA, Yutzey KE (2004) Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Dev Biol 266:1–16.
Gajewski K, Wang J, Molkentin JD, Chen EH, Olson EN, Schulz RA (2003) Requirement of the calcineurin subunit gene canB2 for indirect flight muscle formation in Drosophila. Proc Natl Acad Sci USA 100:1040–1045.
Fossett N, Hyman K, Gajewski K, Orkin SH, Schulz RA (2003) Combinatorial interactions of Serpent, Lozenge, and U-shaped regulate crystal cell lineage commitment during Drosophila hematopoiesis. Proc Natl Acad Sci USA 100:11451–11456.
Nguyen T, Wang J, and Schulz RA (2002). Mutations within the conserved MADS box of the D-MEF2 muscle differentiation factor result in a loss of DNA binding ability and lethality in Drosophila. Differentiation 70:438–446.
Fossett N, and Schulz RA (2001). Conserved cardiogenic functions of the multitype zinc-finger proteins U-shaped and FOG-2. Trends Cardiovasc. Med. 11:185–190.
Fossett N, and Schulz RA (2001). Functional conservation of hematopoietic factors in Drosophila and vertebrates. Differentiation 69:83–90.
Gajewski, K, Zhang, Q, Choi, CY, Fossett, N, Dang, A, Kim, YH, Kim, Y, and Schulz, RA (2001). Pannier is a transcriptional target and partner of Tinman during Drosophila cardiogenesis. Dev. Biol. 233:425–436.
Fossett N, Tevosian SG, Gajewski K, Zhang Q, Orkin SH, and Schulz RA (2001) The Friend of GATA proteins U-shaped, FOG-1, and FOG-2 function as negative regulators of blood, heart, and eye development in Drosophila. Proc Natl Acad Sci USA 98(13):7342–7347.
Fossett N, Zhang Q, Gajewski K, Choi CY, Kim Y, Schulz RA (2000) The multitype zinc-finger protein U-shaped functions in heart cell specification in the Drosophila embryo. Proc Natl Acad Sci USA 97:7348–7353.
Gajewski K, Choi CY, Kim Y, and Schulz RA (2000) Genetically distinct cardial cells within the Drosophila heart. Genesis 28:36–43.
Hsu, T, and Schulz, RA (2000) Sequence and functional properties of Ets genes in the model organism Drosophila. Oncogene 19:6409–6416.
Zars T, Fischer M, Schulz RA, Heisenberg M. (2000) Localization of a short-term memory in Drosophila. Science 288:672–5.
Gajewski K, Fossett N, Molkentin JD, Schulz RA (1999) The zinc finger proteins Pannier and GATA4 function as cardiogenic factors in Drosophila. Development 126: 5679–5688.
Schulz RA, Gajewski K (1999) Ventral neuroblasts and the Heartless FGF receptor are required for muscle founder cell specification in Drosophila. Oncogene 18:6818–6823.
Kremser T, Gajewski K, Schulz RA, Renkawitz-Pohl R (1999) Tinman regulates the transcription of the beta3 tubulin gene (betaTub60D) in the dorsal vessel of Drosophila. Dev Biol 216:327–39.
Choi CY, Lee YM, Kim YH, Park T, Jeon BH, Schulz RA, Kim Y (1999) The homeodomain transcription factor NK-4 acts as either a transcriptional activator or repressor and interacts with the p300 coactivator and the Groucho corepressor. J Biol Chem 274:31543–52.
Mantrova EY, Schulz RA, Hsu T (1999) Oogenic function of the myogenic factor D-MEF2: negative regulation of the decapentaplegic receptor gene thick veins. Proc Natl Acad Sci USA 96:11889–94.
Gajewski K, Kim Y, Choi CY, Schulz RA (1998) Combinatorial control of Drosophila mef2 gene expression in cardiac and somatic muscle cell lineages. Dev Genes Evol 208:382–92.
Cripps RM, Black BL, Zhao B, Lien CL, Schulz RA, Olson EN (1998) The myogenic regulatory gene Mef2 is a direct target for transcriptional activation by Twist during Drosophila myogenesis. Genes Dev 12:422–34.
Lee YM, Park T, Schulz RA, Kim Y (1997) Twist-mediated activation of the NK-4 homeobox gene in the visceral mesoderm of Drosophila requires two distinct clusters of E-box regulatory elements. J Biol Chem 272:17531–41.
Gajewski K, Kim Y, Lee YM, Olson EN, Schulz RA (1997) D-mef2 is a target for Tinman activation during Drosophila heart development. EMBO J 16:515–522.
Schulz RA, Chromey C, Lu M-F, Zhao B, Olson EN (1996) Expression of the D-MEF2 transcription factor in the Drosophila brain suggests a role in neuronal cell differentiation. Oncogene 12:1827–1831.
Ranganayakulu G, Zhao B, Dokidis A, Molkentin JD, Olson EN, Schulz RA (1995) A series of mutations in the D-MEF2 transcription factor reveal multiple functions in larval and adult myogenesis in Drosophila. Dev Biol 171:169–181.
Lilly B, Zhao B, Ranganayakulu G, Paterson BM, Schulz RA, Olson EN (1995) Requirement of MAD domain transcription factor D-MEF2 for muscle formation in Drosophila. Science 267:688–693.