Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Pathway to polycystic kidney disease
  • Lack of cell movement links four developmental disorders
  • Knock down Cbl-b: knock down obstacles to leukemia therapy
  • A Notch(1) in the road to understanding heart valve formation
  • Version history
  • Article usage
  • Citations to this article (0)

Advertisement

Amendment history:
  • Erratum (November 2010)

In this issue Free access | 10.1172/JCI44978

In This Issue

Published October 1, 2010 - More info

Published in Volume 120, Issue 10 on October 1, 2010
J Clin Invest. 2010;120(10):3403–3403. https://doi.org/10.1172/JCI44978.
© 2010 The American Society for Clinical Investigation
Published October 1, 2010 - Version history
View PDF
Pathway to polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the formation of multiple cysts in the kidneys that can cause chronic renal failure. It is caused by mutations in one of two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). The precise molecular mechanisms underlying cystogenesis have not been determined, although some data suggest a role for hyperactivation of mammalian target of rapamycin (mTOR). In this issue (3617–3628), Qin and colleagues delineate the pathway responsible for mTOR hyperactivation in a mouse model of ADPKD and demonstrate that this pathway leads to cystogenesis. Initial analysis indicated that mTOR hyperactivation in Pkd1-null mouse cells occurred downstream of the hepatocyte growth factor (HGF) receptor c-Met. Further analysis revealed that Pkd1-null mouse cells expressed increased levels of c-Met because it was not properly ubiquitinated and degraded. This in turn was because the E3-ubiquitin ligase Casitas B-lineage lymphoma (c-Cbl) was sequestered in the Golgi apparatus. As use of a pharmacologic inhibitor of c-Met inhibited mTOR activity and blocked cystogenesis in a mouse model of ADPKD, the authors suggest that blockade of c-Met could provide a new way to treat individuals with ADPKD.

Lack of cell movement links four developmental disorders

Kallmann syndrome is a developmental disorder characterized by hypogonadotropic hypogonadism and a defective sense of smell as a result of an absence of olfactory bulbs, a condition known as arrhinencephaly. It has been suggested that hypogonadism is caused by failed embryonic migration of neurons producing gonadotropin-releasing hormone 1 (GnRH1) from the nasal epithelium to the forebrain. In this issue (3668–3672), Teixeira and colleagues show that failed embryonic migration of GnRH1-producing neurons is a common feature of several developmental disorders that include arrhinencephaly, specifically X-linked Kallmann syndrome, CHARGE syndrome, trisomy 13, and trisomy 18. Immunohistochemistry analysis of fetuses with these disorders indicated that there were few or no GnRH1-producing neurons in the preoptic and hypothalamic regions of arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. Instead, these cells accumulated in the frontonasal region of the brain, which is the first step of the GnRH neuronal migratory path. As interrupted olfactory nerve fibers were also detected in this region, the authors conclude that the failed migration of GnRH1-producing neurons observed in all four arrhinencephalic disorders studied occurs as a result of a primary embryonic failure of peripheral olfactory structures.

Knock down Cbl-b: knock down obstacles to leukemia therapy

One approach being developed as a treatment for malignant disease is adoptive transfer of ex vivo–expanded autologous tumor-specific CD8+ T cells. Although this approach has been effective in some patients, several issues, including poor in vivo survival and function of the transferred cells, have limited further clinical use. A potential way to improve the efficacy of adoptive immunotherapy is described in this issue by Stromnes and colleagues (3722–3734). In a mouse model of disseminated leukemia, it was found that abrogating expression of Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of lymphocyte activation, in tumor-specific CD8+ T cells expanded ex vivo increased their therapeutic effects upon adoptive transfer. The enhanced therapeutic effects of tumor-specific CD8+ T cells lacking Cbl-b were a result of their restored ability to produce IL-2, decreased threshold for activation, improved survival, and enhanced proliferative responses. As knocking down Cbl-b expression in human CD8+CD28– effector T cell clones had similar in vitro effects, the authors suggest that reducing Cbl-b expression in tumor-specific CD8+ T cells destined for adoptive therapy might improve their therapeutic efficacy.

A Notch(1) in the road to understanding heart valve formation

The most commonly diagnosed congenital heart defects are cardiac valve malformations. Understanding the molecular mechanisms underlying valve development should provide new avenues of research into the origin of cardiac valve defects. In this context, Luna-Zurita and colleagues have determined that integration of endocardial-Notch1 and myocardial-Bmp2 signals in prevalvular regions of the mouse heart is critical to embryonic cardiac valve formation (3493–3507). In higher vertebrates, heart valve primordia are generated from endocardial cells that undergo epithelial-to-mesenchyme transition (EMT). In the study, Luna-Zurita and colleagues show that during cardiac valve formation, EMT is limited to prospective valve territories by the interplay between endocardial-Notch1 and myocardial-Bmp2 to regulate the Snail1 transcription factor. Constitutive Notch1 activity in endocardial cells initiated a partial (noninvasive) Snail1-driven EMT in vitro that became invasive upon Bmp2 treatment. In addition, ectopic myocardial Notch1 expression and loss-of-function experiments indicated that Notch1 represses Bmp2 in cardiac cells while Bmp2 inactivation in the myocardium impaired Notch1 activity. This embryonic Notch1/Bmp2/Snail1 relationship may also be relevant in adult valve disease or atherosclerosis, as these diseases share features such as tissue inflammation, EMT, fibrosis, and calcification.

Version history
  • Version 1 (October 1, 2010): No description

Article tools

  • View PDF
  • Download citation information
  • Send a comment
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article (0)

Go to

  • Top
  • Pathway to polycystic kidney disease
  • Lack of cell movement links four developmental disorders
  • Knock down Cbl-b: knock down obstacles to leukemia therapy
  • A Notch(1) in the road to understanding heart valve formation
  • Version history
Advertisement
Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts