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EDITORIAL FOCUS

Branching out

Department of Medicine and Cell and Molecular Biology Graduate Group, University of Pennsylvania, and Veterans Administration Medical Center, Philadelphia, Pennsylvania

Submitted 26 June 2007 ; accepted in final form 21 July 2007

BRANCHING MORPHOGENESIS IS one the most important processes that occurs during development and allows our many branched organs to form. These include, to name a few, the lungs, liver, pancreas, mammary glands, and kidneys. It has been hypothesized that there is a basic branching morphogenesis "program" that is similar for the different organs and that a specialized function, such as gas exchange in the lungs or solute transfer in the kidneys, is then "layered" onto this basic program. This makes good sense, as it would seem to be a complicated waste of precious resources for evolution to come up with different programs for branching morphogenesis in the lungs vs. kidneys vs. liver, etc. In fact, genes involved in branching morphogenesis in different organs and, indeed, in very different organisms have been described. For example, sprouty is involved in both mammalian kidney branching morphogenesis (2) and branching morphogenesis in the Drosophila trachea (3). The manuscript by Quinlan et al. (10) provides important support for this hypothesis.

Branching morphogenesis during lung development can be divided into early and late events. In early development, the epithelial lung bud undergoes repetitive, dichotomous branching, beginning at 3 wk of gestation. In later stages of development (36 wk of gestation in humans),the lung begins to mature and form the terminal gas exchange units, the alveoli (11). In the kidney, branching morphogenesis begins with the appearance of a small epithelial bud, called the ureteric bud, from the lower end of the mesonephric duct (aka the Wolffian duct) (12). This occurs at 5 wk of gestation, and consecutive dichotomous branching of the ureteric bud occurs 20 times during human gestation, generating the 300,000–1,000,000 nephrons found in each human kidney (7).

Retinoic acid (RA) has been shown to stimulate initial branching of the primary lung bud (6). In 1999, a novel molecule, late-gestation lung protein 1 (Lgl1), was identified in lung fibroblasts (5). Lgl1 mRNA was detected in fetal lung mesenchyme and pulse-chase experiments determined that LGL1 was a secreted mesenchymal glycoprotein that acted on the epithelia (9). When antisense oligodeoxynucleotides were directed against Lgl1, branching of fetal lung explants was inhibited (8). In keeping with the hypothesis that the basic branching morphogenesis program is the same for different organs, Quinlan and colleagues (10) began their studies by examining the role of Lgl1 in kidney branching morphogenesis. They showed that LGL1 protein is expressed in derivatives of the metanephric mesenchyme (but not the epithelial ureteric bud) in the developing kidney. They went on to show that RA stimulates kidney branching morphogenesis, that Lgl1 contains retinoic response elements, and that Lgl1 expression is increased by RA. Finally, they showed that heterozygous Lgl1 knockout mice have decreased branching of the ureteric bud.

The implications of this study, that a protein originally found to be involved in branching morphogenesis in the lungs has similar effects for branching morphogenesis in the kidneys, are profound. A well-accepted in vitro model of branching morphogenesis involves growing Madin-Darby canine kidney cells in a three-dimensional collagen matrix to the cyst stage and stimulating tubulogenesis with hepatocyte growth factor (4). Microarray analysis of this process showed that many hundreds of genes were differentially regulated following the addition of hepatocyte growth factor. Among these genes were known "tubulogenes," such as sprouty, along with many other novel candidate genes (1). If, as the hypothesis suggests, the basic branching morphogenesis program is the same for different organs, this would greatly simplify the determination how this complex process occurs and would obviate the need for testing candidate tubulogenes in every branched organ. It should also lead to novel therapeutic targets. For example, we could branch out and test the ability of genes involved in lung tubulogenesis, to speed the recovery from acute tubular necrosis of the kidney, and to repair the damage in developmental diseases such as the very common CAKUT syndrome (congenital abnormalities of the kidney and urinary tract).

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. H. Lipschutz, 413 Hill Pavilion, 380 S. University Ave., Philadelphia, PA 19104-4539 (e-mail: jhlipsch{at}mail.med.upenn.edu)

	REFERENCES

TOP REFERENCES

 

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2. Basson MA, Akbulut S, Watson-Johnson J, Simon R, Carroll TJ, Shakya R, Gross I, Martin GR, Lufkin T, McMahon AP, Wilson PD, Costantini FD, Mason IJ, Licht JD. Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev Cell 8: 229–239, 2005.[CrossRef][ISI][Medline]
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4. Hellman NE, Greco AJ, Rogers KK, Kanchagar C, Balkovetz DF, Lipschutz JH. Activated extracellular signal-regulated kinases are necessary and sufficient to initiate tubulogenesis in renal tubular MDCK strain I cell cysts. Am J Physiol Renal Physiol 289: F777–F785, 2005.[Abstract/Free Full Text]
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This Article Full Text (PDF) All Versions of this Article: 293/4/F985    most recent 00292.2007v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Lipschutz, J. H. Search for Related Content PubMed PubMed Citation Articles by Lipschutz, J. H.