A. Mechanisms of non-canonical Wnt signaling
Canonical Wnt signaling regulates gene expression through accumulation of -catenin, while non-canonical Wnt signaling is mediated by different signaling molecules, including Rho-family of small GTPases and JNK, to regulate cell polarity, migration and expression of its target genes. We have shown that Ror-family receptor tyrosine kinases mediate non-canonical Wnt signaling by acting as a receptor for Wnt5a, and that Ror2 exhibits both tyrosine kinase-dependent and -independent functions. The goal of this study is to clarify the molecular mechanisms of Ror-mediated non-canonical Wnt signaling, regulating cell polarity and migration, under physiological and pathological conditions, i.e. developmental morphogenesis, regeneration of damaged tissues/organs, cancer invasion/metastasis, and inflammatory diseases.
- Structure-function analysis of Ror-family receptor tyrosine kinases in non-canonical Wnt signaling. Analysis of signaling network containing protein kinases and signaling molecules where Ror serves as a hub.
- Regulatory mechanisms of Wnt5a-Ror signaling by Rho-family of small GTPases.
- Regulatory mechanisms of Wnt5a-Ror signaling by cilia-related proteins.
- Regulatory mechanisms of gene expression by Wnt5a-Ror signaling.
- Regulatory mechanisms of cytoskeletal reorganization by non-canonical Wnt signaling.
B. Wnt signaling in the development of the central nervous system and neurological disorders
We are focusing on how Wnt signaling regulates the developmental processes of the central nervous system (CNS), including the proliferation and differentiation of neuronal cells, neuronal migration, axon outgrowth and synapse formation. We further aim to understand the molecular basis of neurodevelopmental disorders, neurodegenerative diseases and mental disorders through these works. Artificial intervention of Wnt signaling is also of beneficial interest to modulate properly the proliferation and differentiation of neural stem cells / progenitor cells that are applicable to regenerative therapies for the CNS diseases.
- Molecular and cell-biological analysis of proliferation and differentiation of neural stem cells / progenitor cells regulated by Wnt signaling in the developing and adult CNS.
- (Functional analysis of Wnt signaling in axon outgrowth and synapse formation.
- Functional analysis of Wnt signaling in inflammatory response of glial cells.
- Analysis of relationship between aberrant Wnt signaling and neurodevelopmental disorders, neurodegenerative diseases and mental disorders.
- Artificial intervention of Wnt signaling aiming to application of regenerative therapies for the CNS diseases.
C. Regulation of epithelial tubular morphogenesis by Wnt5a-Ror signaling
Studies by our group and others have shown that mice deficient in Wnt5a or Ror1/2 exhibit abnormal morphogenesis in epithelial tubular tissues, including the guts, lungs and kidneys. We are studying how Wnt5a-Ror signaling regulates epithelial tubular morphogenesis by using various knockout and transgenic mice as well as cultured epithelial cells. The goal of this study is to clarify the molecular mechanisms underlying formation and maintenance of epithelial tubular tissues and the relationship between failure of these mechanisms and the pathogenesis of various diseases, including anomalies, chronic inflammation, and cancer invasion/metastasis.
- Molecular basis of elongation and branching of epithelial tubes during mouse kidney development.
- Time-lapse imaging analysis of cellular behavior in organ-cultured mouse embryonic kidney.
- Molecular and cell-biological analysis of epithelial tubular formation and disruption using three-dimensional culture of epithelial cells.
D. Role of Wnt5a-Ror signaling in cancer progression and inflammatory diseases
Overexpression of Wnt5a and/or Ror1/2 is associated with progression or aggressiveness of several types of human cancer, including osteosarcoma, melanoma, breast cancer and lung cancer. Expression of Wnt5a and/or Ror1/2 is also upregulated in pathological conditions associated with chronic inflammation. In fact, using the kidney inflammation/fibrosis model mice, we have shown that expression of Ror2 is induced in the renal epithelial tubules, leading to disruption of the renal basement membrane, a critical step for progression of renal fibrosis. The goal of this study is to clarify the mechanisms by which expression of Wnt5a and Ror is induced under these pathological conditions and its role in the pathogenesis of the diseases at the molecular and cellular levels. We also aim to develop novel diagnosis and therapeutical approaches targeting Wnt5a-Ror signaling.
- Functional analysis of Wnt5a-Ror signaling in cancer invasion and metastasis.
- Functional analysis of Ror1 in acquired resistance of lung cancer cells during chemotherapy.
- Functional analysis of Wnt5a-Ror signaling in cancer progression through interaction with stromal cells.
- Functional analysis of Wnt5a-Ror signaling in proliferation, differentiation and maintenance of stemness of cancer stem cells.
- Regulatory mechanisms of gene expression mediated by Wnt5a and Rors in cancer and chronic inflammatory disorders.
- Functional analysis of Wnt5a-Ror signaling in renal fibrosis and development of novel therapeutical approaches targeting Wnt5a-Ror2 signaling.
E. Regulatory mechanisms of skeletal muscle regeneration after injury by Ror-family of receptor tyrosine kinases
This study aims to elucidate the mechanisms underlying skeletal muscle regeneration after injury, a process that includes activation, proliferation and differentiation (myogenesis) of adult muscle stem cells (satellite cells), and their roles in sarcopenia (age-related muscle loss and atrophy), a serious issue at our aging society, at the molecular and cellular levels. We are trying to uncover the role of Rors in muscle regeneration and the molecular basis of their aberrant expression in several muscle diseases. We also aim to apply our findings to the development of regenerative medicine for muscle loss and atrophy.
F. Elucidation of the fundamental principles of biological phenomena by comprehensive and mathematical analyses
In our research projects described above (A-E) or related projects, elucidation of the nature of plasticity and the fundamental principles of biological systems needs comprehensive and mathematical approaches, such as metabolomic analysis and modeling/simulation of cell behaviors with high spatio-temporal resolution, respectively. By employing these approaches we will try to innovate a novel research field.