Research Interests
We are studying the molecular mechanisms that are involved in the induction and patterning of early vertebrate embryo. To begin to identify the molecular pathways involved in early development, we are examining the endogenous role of genes initially identified based on their implication in human disease. Recently, it has been shown that patients with the Noonan syndrome frequently have mis-sense mutations in the nonreceptor phosphatase Shp-2, a gene required downstream of FGF in the MAPK signaling cascade. Clinical studies have demonstrated that Noonan syndrome, is a relatively common autosomal dominant disorder that leads to a number of developmental abnormalities including atrial septal defects, ventricular septal defects, and hypertrophic cardiomyopathy, and is associated with juvenile myelomonocytic leukemia and acute myeloid leukemia. Recently it was demonstrated that approximately 50% of patients with Noonan syndrome have mutations in a defined region of SHP-2. Interestingly, all are mis-sense mutations and map to a SH2 domain, a region of SHP-2 required for protein-protein interactions and involved in switching the protein from an inactive to active state, and hence the mutations are thought to act in a dominant negative fashion. To elucidate the molecular mechanisms by which this single gene functions in such diverse cellular pathways during normal development and in human disease, we are undertaking a comparative genomic approach in Xenopus and mouse to construct an allelic series of SHP-2 in vivo. Thus, coupling the experimental embryology and molecular techniques in frogs with genetic analysis in the mouse. In addition, we have constructed inducible versions of wild type and mutant forms of SHP-2 identified in Noonan syndrome patients, and are introducing these into Xenopus and mouse to determine the precise time at which SHP-2 functions. Through these approaches, we will be able to define and characterize the cellular and biochemical pathways through which SHP-2 functions.

A second human congenital human disease that shares overlapping clinical features with Noonan syndrome is the Holt-Gram syndrome (HGS), a disease associated with mutations in the coding region of the transcription factor TBX5. Like Shp-2, TBX5 has also been demonstrated to be required for limb and heart development, suggesting the two proteins may function in the same cellular or molecular pathway. TBX5 is a member of the T -box genes that encodes a family of transcription factors that share a characteristic sequence similarity within the DNA-binding domain (T-domain). To date, eighteen different mammalian T-box genes have been identified, many of which have orthologues in a wide variety of multicellular organisms. The role of individual family members in early development and human disease is emphasized by clinical studies demonstrating that mutations in T -box genes are associated with numerous disease states in humans, including congenital diseases such as the DiGeorge and Holt-Gram syndromes, and by the observation that T -box genes are amplified in a subset of cancers. A second major goal of our work is to identify and characterize the molecular relationship between the MAPK/SHP-2 pathway and specific members of the T-box gene family, and in particular TBX5. Consistent with the hypothesis that TBX5 and SHP-2 may function in the same cellular or molecular pathway, we have shown a direct link between the FGF/MAPK signal transduction pathway and TBX5 transcriptional activity. Moreover, we have shown that SHP-2 can lead to ectopic expression of TBX5. We are now investigating the pathways that link the two proteins. Through these approaches, we will be able to define and characterize the cellular and biochemical pathways through which SHP-2 functions both in normal development and in human disease.

Training
Nasson College, B.S., 1981, Chemistry
Columbia University, M.A., 1989, Department of Genetics & Development
Columbia University, M. Phil., 1991, Department of Genetics & Development
Columbia University, Ph.D., 1994, Department of Genetics & Development
National Institute for Medical Research, Mill Hill, Post-doctoral, 1994-2000
Dr. Jim Smith, London, UK, Fellow, Laboratory of Developmental Biology

Publications
Conlon, F. L., Barth, K.S., and Robertson, E. J. (1991) A novel retrovirally induced embryonic lethal mutation in the mouse: Assessment of the developmental fate of embryonic stem cells homozygous for the 413.d proviral integration. Development 111 :969-981.

Robertson, E. J., Conlon, F. L., Barth, K. S., Costantini, F., and Lee, J. (1992) Use of embryonic stem cells to study recessive lethal mutations in the mouse. In Post-implantation development in the mouse. CIBA Foundation Symposium 165, pp 237-250. 1. Marsh, editor. John Wiley and Sons, Ltd.

Conlon, F. L., Lyons, K. M., Takaesu, N., Barth, K. S., Kispert, A., Herrmann, B., and Robertson, EJ. (1994) A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120:1919-1928.

Ruiz, J. C., Conlon, F. L., and Robertson, E. J. (1994) Identification of a novel protein kinase expressed in the myocardium of the developing heart. Mechanisms of Development 48: 153-164.

Conlon, F. L., Wright, C. V. E., and Robertson, E. J. (1995) Effects of the Twis mutation on notochord formation and mesodermal patterning. Mechanisms of Development 49:201-209.

Conlon, F. L. and Beddington, R. (1995) Mouse gastrulation from a frog's perspective. Seminars in Developmental Biology 6:249-256.

Morgan, B. A., Conlon, F. L., Manzanares, M., Millar, 1. B. A., Krumlauf, R., Smith, J. C., and Sedgwick, S. (1996) Transposon tools for recombinant DNA manipulation: Characterization of transcriptional regulation from yeast, Xenopus, and mouse. Proceedings of the National Academy of Science USA 93:2801-2806.

Conlon, F. L., Jones, C. M., and Smith, J.e. (1996) From mouse to frogs: identification and functional analysis of genes required for formation and patterning of the mesoderm. Seminars in Cell and Developmental Biology 7:95-101.

Conlon, F. L., Sedgwick, S., Weston, K., and Smith, 1.C. (1996) Inhibition of Xbra transcriptional activation causes defects in mesodermal patterning and reveals autoregulation in dorsal mesoderm. Development 122:2427-2435.

Smith, 1. C., Armes, N. A., Conlon, F. L., Tada, M., Umbhauer, K. M., and Weston, K. (1997) Upstream and downstream of Brachyury, a gene required for vertebrate mesoderm formation. Cold Spring Harbor Symposium of Quatitative Biology 62:337-346.

Casey, E., O'Reilly, M-A., Conlon, F. L., and Smith, J.C. (1998) The T-box transcription factor Brachyury regulates expression of eFGF through binding to a non-palindromic response element. Development 125: 3887-3894.

Conlon, F. L. and Smith, J.C. (1999) Interference with brachyury function inhibits convergent extension, causes apoptosis, and reveals separate requirements in the FGF and activin signalling pathways. Developmental Biology 213:85-100.

Smith JC, Conlon FL, Saka Y, Tada M. (2000) Xwntll and the regulation of gastrulation in Xenopus. Philos Trans R Soc Lond B Bioi Sci. 2000 JuI29;355(1399):923-30.

Conlon, F.L. and Kessler, D.S. (2000) Hopping into the new millennium. TIGS 16,537-540.

Conlon, F. L., Casey, E., Price, B., and Smith, J.C. (2001) Transcriptional specificity of the T-box Proteins. Development 128, 3749-3758.

Wilson, V. and Conlon, F.L. (2001) Tbox Gene Family. Genome Biology May 20023(6): Review.

Brown, D. D., Binder, 0., Pagratis, M., Parr, B., Conlon, F.L. Developmental expression of the Xenopus Tbx20 Orthologue. (2002) Dev. Genes and Evo\. (Dev Genes Evo\. 212, 604-607. ).

Moser, M., Binder, 0., Wu, Y, Aitsebaomo, Bode, C., Bautch, V., Conlon, F. L., Patterson, C. (2003) BMPER, a novel endothelial cell precursor-derived protein, antagonizes BMP signaling and endothelial differentiation. MCB 23: 16,5664-5679.

Conlon, F. L., Showell, c., and Binder, O. T-box genes and early mesodermal patterning. Dev. Dyn. (In Press).

Sparrow, D. B. and Conlon, F. L. Library construction and screening: Libraries for isolating interacting proteins. In Multimedia methods in molecular biology. Partridge, T., Jones, P. and Rickwod, D., editors. Chapman & Hall/CRC Press. (In press)

E-mail: frank_conlon@med.unc.edu
Telephone: 919-843-5500
Address: 222 Fordham Hall Chapel Hill, NC

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