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Organogenesis -Molecular mechanisms of kidney development

Our research interest is to elucidate molecular mechanisms in organogenesis, especially kidney development. We also aim at derivation of kidney progenitors from stem cells, by utilizing knowledge obtained from molecular genetics.

The kidney develops in three stages: pronephros, mesonephros, and metanephros.Ê Many of the genes expressed in the metanephros are also found in the pronephros. Animal caps, a presumptive ectoderm of Xenopus embryos at the blastula stage, differentiate into three-dimensional pronephric tubules in three days in chemically defined saline solution upon treatment with activin and retinoic acid. We have used this system to identify molecules expressed in pronephros and potentially in mesonephros and metanephros. One of the genes we isolated was Xsal-3, a newly identified sal member of Xenopus, which was expressed in the pronephros and the brain. We then cloned a member of the murine sal family from the developing kidney, which proved to be a mouse homolog of human SALL1.

SALL1 is a mammalian homolog of the Drosophila region-specific homeotic gene spalt (sal) and heterozygous mutations in SALL1 in humans lead to Townes-Brocks syndrome. We isolated a mouse homolog of SALL1 (Sall1) and found that mice deficient in Sall1 die in the perinatal period and that kidney agenesis or severe dysgenesis are present. Sall1 is expressed in the metanephric mesenchyme surrounding ureteric bud and homozygous deletion of Sall1 results in an incomplete ureteric bud outgrowth, a failure of tubule formation in the mesenchyme and an apoptosis of the mesenchyme. This phenotype is likely to be primarily caused by the absence of the inductive signal from the ureter, as the Sall1 deficient mesenchyme is competent regarding epithelial differentiation. Therefore Sall1 is essential for ureteric bud invasion, the initial key step for metanephros development.

We are currently examining molecular functions of Sall1. In addition, we are trying to establish an induction system of kidney progenitors from a variety of cell sources, and also in vitro and in vivo assays for kidney progenitors. Our final goal is to understand molecular mechanisms of kidney development and to utilize the knowledge for derivation of kidney progenitors for cell therapy.

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Fig.2
Fig.1 Kidney development.

Kidney development is divided in three stages: pronephros, mesonephros, and metanephros (kidney in adult). Animal caps of Xenopus embryos, which are treated with activin and retinoic acid, give rise to pronephric tubules in three days. Utilizing this system, we have cloned several genes both in frogs and in mice, and are analyzing their functions in kidney development. We also plan to isolate kidney progenitors and establish differentiation systems in vitro and in vivo.

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Fig.1
Fig.2 Self-renewal signal transduction in ES cells

LIF, a self-renewal factor for ES cells, regulates several signaling pathways in ES cells. We have found that STAT3 activation is necessary and sufficient for maintenance of undifferentiated ES cells. Now we are trying to identify the target (s) of STAT3 to understand the self-renewal mechanism of ES cells.

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last updated on 5/28/2004.