Our goal is to define the molecular mechanisms responsible for organ development, regeneration, and maintenance using mutant fish and knockout mice. To accomplish this goal, we have focused on defining signaling molecules and metabolic cues that regulate liver and brain formation and maintenance. Our studies will provide new insights into the precise molecular mechanisms that underlie organ failures found in human diseases and will lead to the development of new rational therapies for these disorders.
1. Research on early embryogenesis
Fertilized mammalian eggs repeatedly undergo cell division to generate the outer, middle, and inner germ layers that form the basis of organs. Through dynamic processes of cell migration and differentiation, the ectoderm arises from the upper layer of the blastoderm, and the mesoderm and endoderm form from the primitive streak. The primitive streak is therefore called the " first step towards cell differentiation" and is an extremely important tissue that initiates ontogeny. However, in the uterus of a pregnant mouse, the primitive streak is such a tiny tissue that it is difficult to analyze. Thus, there remain many questions about the molecular mechanisms driving the formation of the primitive streak. To address these questions, we have used mouse embryonic stem (ES) cells to generate a population of primitive streak-like cells. We have also established an experimental system to induce the differentiation of these cells into beating myocardial cells (derived from mesoderm), albumin-producing hepatocytes (derived from endoderm), and neurons that extend axons. Using this system, we have been successful in identifying various signaling molecules and metabolites required for primitive streak formation and differentiation.
2. Research on organogenesis
The individual sizes and shapes of living organisms are greatly influenced by earth”Ēs gravity. However, the mechanism by which organisms resist gravity to maintain these properties is largely unknown. Similarly, it is unclear why the organs of an individual organism perform their functions well only when they are properly sized and arranged in an orderly manner. To address these important issues, we have generated appropriate models by isolating gravity-sensitive medaka mutants and creating knockout mice. For example, using our gravity-sensitive medaka mutant, we unexpectedly discovered that the Hippo-YAP pathway plays an essential role in three-dimensional organogenesis. As a result of this information, we are currently analyzing the role of the Hippo-YAP pathway in mouse liver formation.
3. Research on organ homeostasis
Damage or senescence in cells can promote diseases such as cancer. Therefore, these abnormal cells need to be removed in order to maintain organ homeostasis. However, the mechanism by which these abnormal cells are eradicated is largely unknown. Using cultured cells derived from mouse liver or canine kidney, we have found that the Hippo-YAP pathway is involved in the elimination of abnormal cells. In a parallel project, we have shown that the MKK7-JNK pathway is essential for the constitutive functions of the mouse brain. We are analyzing the roles of these signaling pathways in maintaining the homeostasis of the mammalian liver and brain.