Vertebrate Developmental Biology
In our research, we are studying developmental signals in the establishment of the embryonic body plan, nervous system and pancreas. Particular emphasis is given to mechanisms that regulate retinoic acid (RA) and fibroblast growth factor (FGF) signaling in the frog Xenopus laevis and the mouse. The enzyme retinol dehydrogenase-10 (Rdh10) has an important role in the biosynthesis of RA from vitamin A. We previously reported that Rdh10 contributes to graded RA signaling in body axes and brain development of the Xenopus embryo. We also showed that Rdh10 is essential for localized RA production in the development of the pancreas and differentiation of endocrine cells in the mouse embryo. Cell surface proteoglycans (PGs) regulate FGF signaling through binding of FGFs to glycosaminoglycan chains. We described that the secreted serine protease HtrA1 cleaves PGs and stimulates FGF signaling in tail formation. We also showed that the secreted serine protease inhibitor SerpinE2 (Protease Nexin-1) promotes head development by binding to and inhibiting HtrA1, thus protecting the integrity of PGs and restricting FGF signaling. The neural crest is a multipotent and highly motile cell population in the vertebrate embryo. More recently we reported that chondroitin/dermatan sulfate glycosaminoglycan chains have an important role in neural crest cell migration.
To investigate the molecular control of cell migration in the embryonic neural crest
To identify new diagnostic markers and drug targets in neuroblastoma
Our experimental and genetic studies on cell signaling in animal models has important implications for human development and diseases, including diabetes, cancer and rare diseases. Glucagon-producing alpha and insulin-producing beta cells are key regulators of blood glucose. Our finding that Rdh10/retinoic acid is essential for the differentiation of these endocrine cells in the developing mouse pancreas is of high relevance to diabetes. HtrA1 is a well-established tumor suppressor in several cancers, and misregulation of this secreted serine protease has been linked to arthritis, CADASIL, macular degeneration, and Alzheimer’s disease. Our study in Xenopus embryos showed that HtrA1 through cleaving proteoglycans mobilizes FGF-proteoglycan messages, allowing long-range FGF signaling to occur. This process is regulated by SerpinE2, which to our knowledge is the first endogenous inhibitor of HtrA1. In addition, we found that chondroitin/dermatan sulfate biosynthesis correlates with tumorigenic properties in melanoma and neuroblastoma. 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