Role of typeIII receptor tyrosine kinases in lympho-hematopoietic tissues

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This grant covered three projects to understand the molecular mechanisms underlying development of lymphohematopoietic tissues in the embryo. Followings are the summary of our progress.1) We attempted to define all intermediate stages in the differentiation pathway towards hematopoietic and vascular endothelial cells. For this purpose, we developed mAbs recognizing PDGFRalpha, c-Kit and Flkl that are expressed distinct subsets of nascent mesoderm of mouse embryo. These surface markers in combination with E-cadherin, V-cadherin, CD34, CD31 and CD45 were successfully used to define probably all possible intermediate stages. We are currently investigating the molecular mechanisms regulating each branching point in this differentiation pathway.2) Cellular and molecular basis for peyer's patch formation was investigated. While molecular requirements for peyer's patch formation has been elucidated through the analysis of various KO mice, it has been unclear how these molecules like lymphotoxins are involved in the formation of peyer's patch analage. Using IL-7Ralpha-KO mice and an antagonistic anti-IL-7Ralpha-mAb, we found that IL-7Ralpha^+ immature lymphocytes are the inducer of the peyer's patch anlage. This study demonstrated for the first time that immature lymphocyte has its own unique function. Based on this finding, we succeeded to produce mice that lacks peyer's patch but otherwise normal. This model mice will be helpful to understand the role of peyer's patch in the mucosal immunity.3) In an attempt to understand the development of hematopoietic microenvironment, we found that PDGFRalpha is expressed in the stromal cell component of the fetal liver on which hematopoietic cells are associated. Using Ph/Ph mutant mice that lacks this molecule, we found that adult-type erythropoesis was not initiated in the absence of PDGFRalpha.