Vertebrate Developmental Biology
In our research, we are studying extracellular signals in embryonic development and cancer. Particular emphasis is given to mechanisms that regulate pattern formation and collective cell migration in the vertebrate embryo. The neural crest is a multipotent and highly motile cell population that arises at the border of the neural plate, delaminates and colonizes a wide variety of tissues and organs. Defects in neural crest development, which are collectively referred to as neurocristopathies, include tumors of neural crest lineages, such as neuroblastoma and melanoma. Because of its high number of large embryos and external development, the African claw frog Xenopus laevis is our favorable experimental system.
Cell surface proteoglycans regulate fibroblast growth factor (FGF) signaling through binding of FGFs to glycosaminoglycan chains. We previously reported that the secreted serine protease HtrA1 by cleaving proteoglycans liberates FGF-proteoglycan messages from the cell surface and stimulates long-range FGF signaling during germ layer formation and body axis development in the Xenopus embryo. We also showed that the secreted serine protease inhibitor SerpinE2 (Protease Nexin-1) binds to and inhibits HtrA1, thus protecting the integrity of proteoglycans and restricting FGF signaling. Both HtrA1 and SerpinE2 are transcriptionally activated by FGF signals suggesting autocatalytic feedback regulation. More recently we reported that chondroitin/dermatan sulfate glycosaminoglycan chains have an important role in neural crest cell migration and adhesion to the matrix protein fibronectin. This study also demonstrated that chondroitin/dermatan sulfate biosynthesis correlates with tumorigenic properties in neuroblastoma and melanoma.
To investigate the molecular control of cell migration in the embryonic neural crest
To establish new diagnostic markers and drug targets in neural crest-derived cancers
Embryonic development and tissue remodeling rely on tightly controlled growth factor signaling and the coordinated movement of cells to specific locations. The study of collective cell migration helps to design effective ways to prevent cancer metastasis, improve wound healing or contribute to new ways for ex vivo organ development in regenerative medicine. FGFs and their receptors have a wide range of cellular functions, and there is increasing evidence for the importance of FGF signaling in the pathogenesis of various tumors. HtrA1 is a well-established tumor suppressor protein in several cancers, and misregulation of this secreted serine protease has been linked to arthritis, neurodegenerative diseases and pregnancy disorders. SerpinE2 is a putative oncogene and plays important roles in the nervous system, blood and reproductive systems. Our identification of HtrA1 as a feedforward stimulator and SerpinE2 as feedback inhibitor of FGF signals suggests a new level of extracellular growth factor regulation that might not be restricted to the Xenopus embryo but also relevant for human development and diseases, including cancer. The molecular analysis of neural crest migration will improve our understanding of neurocristopathies and help to develop therapeutic strategies. Our finding that embryonic neural crest cell migration depends on chondroitin/dermatan sulfate further suggests that neural crest defects might account for craniofacial malformations in the musculocontractural Ehlers-Danlos syndrome, adding this rare connective tissue disease to the list of neurocristopathies.
(name linked to profile in Lund University research portal)
Principal Investigator, Edgar [dot] Pera [at] med [dot] lu [dot] se
Student, iv3817mi-s [at] student [dot] lu [dot] se
Student, bmp12jni [at] student [dot] lu [dot] se