Regenerative Medicine and Developmental Biology

Children's Research Institute and The Medical College of Wisconsin have developed a vigorous and growing program in developmental biology and regenerative medicine. The program consists of 22 laboratories studying diverse aspects of embryogenesis and stem cell biology.

What is developmental biology?

Understanding the molecular mechanisms that control how an embryo is formed following fertilization is essential to realize the potential of stem cells as therapies to treat common diseases such as diabetes, hypertension, metabolic disease and even cancer. To discover the processes that cause congenital disease requires a thorough understanding of how tissues and cells formed during gestation. A thorough appreciation of the basics of developmental biology will produce novel treatments and diagnostics that directly impact health care.

During the last 10 years, a concentrated effort has been made by the institute to expand in areas of biomedical research that aim to unravel the fundamental mechanisms through which human beings develop. This has resulted in the recruitment of several leading researchers in the areas of stem cell biology, cardiogenesis, vasculogenesis and hepatogenesis. Recruitment also included specialists in the development of the gastrointestinal tract, kidney, ear, eye and nervous system. This group of internationally renowned scientists and clinicians has attracted extensive funding from the National Institutes of Health and private sources. They have published hundreds of original research articles and have trained dozens of postdoctoral fellows and graduate students.

What is regenerative medicine?

The goal of regenerative medicine is to use stem cells in the study of cell biology, developmental biology and disease. The program provides the infrastructure and expertise to help investigators integrate the culture and differentiation of embryonic stem cells into their research programs. The program actively is involved in recruiting stem cell researchers whose programs have the potential to complement and extend existing research endeavors. The program also administers a forum for investigators whose focus is developmental biology and/or stem cell research. This weekly forum allows them to promote, share and discuss cutting-edge unpublished findings with colleagues. In addition, the program invites renowned stem cell biologists to present their research on a regular basis.

Alan N. Mayer, MD, PhD, lab

Information about how organs are formed during embryonic development is contained within the genetic code. The Alan N. Mayer, MD, PhD, research lab aims to identify the codes that are essential for making organs and to integrate gene function into a general mechanistic framework for organogenesis. As a starting point, the lab is taking a classical genetics approach using zebrafish for mutational analysis.

By isolating mutation with defects in organ development, genes that are defective can be tracked down. Once identified, a gene can be studied in several different respects.

Taking this approach, the lab has identified at least six genes with essential roles in the development of the intestine. One of these encodes is a protein called NPO, which is a novel RNA-binding protein of unknown function. One of the main projects in the lab is to understand how NPO works. Investigators also are studying NPO in the mouse since organ development in the mouse differs compared to the fish. Investigators also are searching for new genes that regulate key developmental processes and have mapped five other mutations. The real work begins when the mutation is identified since the genes' identity does not always reveal the molecular pathway of its action. This approach will lead to advances in the field of organ development.

Neural crest is a multipotent stem cell population that can give rise to a wide range of derivatives including neurons and glia of the peripheral nervous system, pigment cells and craniofacial skeleton. Because many tissues receive contributions from the neural crest, defects in migration and differentiation can lead to severe birth defects and malignant cancers.

Investigators in the laboratory are interested in the cellular and molecular mechanisms that control cell fate commitment, migration and differentiation of neural crest cells.

Current projects include studying:

• Mechanisms underlying the formation of the peripheral nervous system by examining the role of sphingosine-1-phosphate signaling during gangliogenesis and differentiation of dorsal root ganglion neurons.
• Neural crest cell differentiation during craniofacial development by characterizing a novel growth factor that is involved in chondrogenesis. Research is challenging the developmental potential of migrating neural crest cells by heterotopic and heterochronic transplantations and by examining the interactions between these progenitor cells and microenvironment in vivo.

Elena Semina, PhD, laboratory

This laboratory applies molecular genetic approaches to identify genes that interfere with human development, with the goal of understanding mechanisms of normal and aberrant development and better management of associated human disorders.

Elena Semina, PhD, focuses on the Pitx family of homeodomain-containing transcription factors, which play an important role in the development of multiple organs including the anterior segment of the eye, craniofacial region, brain, heart and umbilical area. The PITX2 gene was identified by positional cloning as a gene involved in Axenfeld-Rieger syndrome, a congenital condition characterized by the anterior segment anomalies with glaucoma and also dental and umbilical defects. The PITX3 gene was found to be responsible for Peters' anomaly/anterior segment dysgenesis phenotype and cataracts in humans and aphakia in mice.

Ocular development in Pitx2- and Pitx3-mutant mice is arrested at the stage of lens vesicle formation and its separation from the corneal ectoderm, which normally induces development of the anterior segment structures. Abnormal development of the anterior segment of the eye often leads to blindness due to glaucoma, corneal opacities or cataracts. The molecular mechanisms responsible for normal development of the anterior segment of the eye are not well defined and studies of Pitx genes' pathways present the unique opportunity to approach these processes. Primary institute efforts are directed toward identification of factors involved in regulation of PITX expression as well as downstream targets genes. The continuing goal is development of animal models of glaucoma and other ocular disorders for in vivo examination of the pathologic processes and genetic identification of secondary factors contributing to disease severity.