Associate Member of Staff
Director
Forsyth Center for Regenerative and Developmental Biology
Assistant Professor, Department of Surgery, Harvard Medical School
email:
Harvard University, Ph.D., 1998, Developmental Oral Biology
Organogenesis depends upon a well-ordered series of inductive events involving coordination of molecular pathways that regulate the generation and patterning of specific cell types. A key question in organogenesis is the identification of the molecular mechanisms by which proteins interact to organize distinct pattern formation and cell fate determination. The fundamental understanding of the control mechanisms responsible for normal patterning in the embryo will help us understand cell fate specificity and may provide valuable information towards organ regeneration.
The focus of the Bei lab is on the elucidation of mechanisms controlling mammalian organogenesis. Using mouse as our main experimental system and a variety of classic embryological techniques, combined with targeted mutagenesis and molecular biology, our research program is devoted to understanding the molecular genetics of organ formation in vertebrates and in particular the formation and homeostasis of the skin and its appendages.
Our studies in the past have shown that one class of genes, the Msx genes, controls the formation and homeostasis of epithelial appendages through an Msx-controlled genetic hierarchy, where several families of growth and transcription factors are involved. An important finding to emerge from these studies is that early formation of epithelial organs appears to be controlled by conserved regulatory gene-cascades. The extent, however, to which pathways are common between organs is still preliminary. Moreover, the vast majority of genes involved and the molecular mechanism by which these molecules interact to organize distinct pattern formation and to determine cell fate are still unknown.
In that context, using recent advances in genomics and high-throughput technologies, we are currently involved in the identification of novel genes and pathways whose function is important to ectoderm-derived organs. We have identified several families of signaling and transcription factors that are deregulated upon depletion of Msx1 or Msx2 function, using as our model systems, the skin, the developing tooth, nail and the hair cycle, that are affected in Msx1 and Msx2 mutant mice, respectively.
In addition to the expression profiling studies and in order to understand the molecular mechanism by which Msx proteins regulate downstream gene expression, functional analysis of the Msx homeodomain looking at both protein-protein interactions and DNA binding has been conducted. It is believed for example that Msx transcription factors interact through their homeodomain with components of the basal transcription apparatus and other homeoproteins. However, the in vivo relevance of these protein-protein interactions is unknown. Moreover, the functional activity of Msx proteins, whether they act as activators or repressors or as both is not yet well understood.
To address this important question, we test the hypothesis that Msx’s activity, as a repressor or activator, is modulated by interactions with specific partners, depending on the developmental context. Using in vivo and in vitro approaches, we have identified several transcription factors that mediate protein-protein interactions with Msx, in a context-dependent manner.
The activity of transcription factors is also tightly modulated by post-translational modifications affecting stability, localization, and protein-protein interactions. Conjugation to SUMO, for example, is a reversible post-translational modification of transcription factors that regulates functions involved in cell proliferation, differentiation and organogenesis. Considering that, we have recently shown that at least the first member of the Msx family of transcription factors, the Msx1, is sumoylated in vivo and that sumoylation interferes with the ability of Msx1 to interact with specific partners, sumoylation emerges as an important regulatory mechanism for protein-protein interactions and transcription regulation, in general.
In sum, the studies, described above, provide a molecular framework and an important insight on the function of Msx under physiological conditions, on the transcriptional mechanism regulating epithelail organ formation and on the pathogenetic mechanisms of certain types of ectodermal dysplasia diseases.
Our research is committed to creating a program where basic understanding of the genetic pathways and molecular mechanisms controlling ectodermal organ formation and homeostasis can be put to practical use in clinical settings, particularly in the context of ectodermal organ regeneration and skin abnormalities. In doing so, we can create a platform for bringing developmental biology to medicine, creating, thus, an environment where clinical and basic science researchers can be trained and put innovative ideas into practice.
Bei M. (2009) Molecular genetics of tooth development. Curr. Opin. Genet. Dev. 19(5):504-510.
Bei M.(2009) Molecular genetics of ameloblast cell lineage. J. Exp. Zool. B Mol. Dev. Evol. 312B(5):437-444.
Gupta V, Bei M. (2006) Modification of Msx1 by SUMO-1. Biochem. Biophys. Res. Commun. 345(1):74-77.
Aberg T, Wang X, Kim J, Yamashiro T, Bei M, Ryoo H, Thesleff I. (2004) Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Dev. Biol. 270(1):76-93.
Bei M, Stowell S and Maas R. (2004) Msx2 controls ameloblast terminal differentiation. Dev. Dyn. 231(4): 758-765.
Intan Ruspita, Ph.D.
Irfan Saadi, Ph.D.
Minglian Zhao, Ph.D.
FCRDB/Bei Lab Manager
Yan Xia, M.D.
.
