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To bud or not to bud: the RET perspective in CAKUT

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Abstract

Congenital anomalies of the kidneys or lower urinary tract (CAKUT) encompass a spectrum of anomalies that result from aberrations in spatio-temporal regulation of genetic, epigenetic, environmental, and molecular signals at key stages of urinary tract development. The Rearranged in Transfection (RET) tyrosine kinase signaling system is a major pathway required for normal development of the kidneys, ureters, peripheral and enteric nervous systems. In the kidneys, RET is activated by interaction with the ligand glial cell line-derived neurotrophic factor (GDNF) and coreceptor GFRα1. This activated complex regulates a number of downstream signaling cascades (PLCγ, MAPK, and PI3K) that control proliferation, migration, renewal, and apoptosis. Disruption of these events is thought to underlie diseases arising from aberrant RET signaling. RET mutations are found in 5–30 % of CAKUT patients and a number of Ret mouse mutants show a spectrum of kidney and lower urinary tract defects reminiscent of CAKUT in humans. The remarkable similarities between mouse and human kidney development and in defects due to RET mutations has led to using RET signaling as a paradigm for determining the fundamental principles in patterning of the upper and lower urinary tract and for understanding CAKUT pathogenesis. In this review, we provide an overview of studies in vivo that delineate expression and the functional importance of RET signaling complex during different stages of development of the upper and lower urinary tracts. We discuss how RET signaling balances activating and inhibitory signals emanating from its docking tyrosines and its interaction with upstream and downstream regulators to precisely modulate different aspects of Wolffian duct patterning and branching morphogenesis. We outline the diversity of cellular mechanisms regulated by RET, disruption of which causes malformations ranging from renal agenesis to multicystic dysplastic kidneys in the upper tract and vesicoureteral reflux or ureteropelvic junction obstruction in the lower tract.

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Acknowledgments

We thank Dr. Feng Chen for many useful comments and discussions in preparation of this manuscript. We apologize to all colleagues if we overlooked to cite their work. Work reported in this review was partly supported by the National Institutes of Health grants DK081644 and DK082531 (S.J.).

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  1. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA

    T. Keefe Davis

  2. Department of Internal Medicine (Renal Division), Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Box 8126, St. Louis, MO, 63110, USA

    Masato Hoshi & Sanjay Jain

  3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Sanjay Jain

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  1. T. Keefe Davis
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Correspondence to Sanjay Jain.

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Davis, T.K., Hoshi, M. & Jain, S. To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol 29, 597–608 (2014). https://doi.org/10.1007/s00467-013-2606-5

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