JCI online early table of contents: Nov. 2, 2009

November 02, 2009

EDITOR'S PICK: Disrupting male fertility

The sexual function of male rodents can be impaired by in utero and/or neonatal exposure to external molecules that disrupt normal hormone functioning, giving rise to concerns that low-level exposure to such molecules might cause similar effects in humans. Examples of such molecules include the synthetic nonsteroidal estrogen DES, which was used as a treatment for various diseases until the mid 1990s, and BPA, which is found, among other places, in some plastic containers. New research, by David H. Volle and colleagues, at INSERM U895, France, has identified the molecular mechanism underlying many of the harmful effects of DES on the mouse testis.

The pivotal experiments demonstrated that neonatal exposure to DES led to a much more dramatic reduction in fertility in male mice with the protein NR0B2 than it did in male mice lacking the protein because NR0B2 deficiency protected male mice against the negative effects of DES on testis development and function. NR0B2 deficiency also protected male mice from the detrimental effects of postnatal and adult exposure to DES. Future work will determine whether similar pathways link human exposure to molecules such as DES that disrupt normal hormone functioning to the increased incidence of male reproductive disorders.

TITLE: The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice

David H. Volle
Unité INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet 2, Nice, France.
Phone: 33-4-89-06-42-52; Fax: 33-4-89-06-42-60; E-mail: david.volle@inserm.fr.

View this article at: http://www.jci.org/articles/view/38521?key=fxLBS5XoK4vz541wU3I8

EDITOR'S PICK: Modifying neural stem cells improves their therapeutic efficacy

Stem cells isolated from the brain of adult mice (adult neural stem cells [aNSCs]) have shown very modest therapeutic effects in a mouse model of the chronic inflammatory neurodegenerative disease multiple sclerosis. But now, Guang-Xian Zhang and colleagues, at Thomas Jefferson University, Philadelphia, have developed an approach to enhance the therapeutic effects of aNSCs in this model of multiple sclerosis. Specifically, the researchers genetically engineered aNSCs to express the anti-inflammatory molecule IL-10 and found that these cells induced more extensive functional and pathological recovery from ongoing disease than did nonengineered aNSCs. Importantly, the IL-10-aNSCs mediated their effects in multiple ways, suppressing immune system attack of nerve cells, promoting nerve cell repair, and promoting production of the nerve cell protective sheath. The authors hope these results might increase the chance that aNSC-based therapies might one day be developed for clinical use.

TITLE: Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis

Guang-Xian Zhang
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: (215) 955-8935; Fax: (215) 503-5848; E-mail: Guang-Xian.Zhang@jefferson.edu.

View this article at: http://www.jci.org/articles/view/37914?key=NKxgD7l4U2cHdaVxIjn7

EDITOR'S PICK: New genetic cause of a fatal immune disorder

Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, fatal, immune disorder characterized by uncontrolled activation of immune cells known as lymphocytes and macrophages. Disease-causing mutations have been identified in several genes that generate proteins involved in lymphocyte-mediated cell death, including syntaxin-11. Now, Geneviève de Saint Basile and colleagues, at INSERM U768, France, have added a new gene to this list by determining that two distinct mutations in the gene that generates syntaxin-binding protein 2 (Munc18-2; also known as STXBP2) cause disease in a subset of patients with FHL; this form of the disease was then termed 'FHL5'.

Mechanistically, the two distinct STXBP2 mutations led to substantially decreased STXBP2 protein in patient lymphoblasts and impaired release of death-inducing molecules from immune cells known as NK cells. Further analysis indicated that the predominant protein to which STXBP2 binds in lymphocytes is syntaxin-11. The authors therefore conclude that STXBP2 binds syntaxin-11, thereby controlling a late step of the secretory pathway that releases death-inducing molecules; in patients with FHL5, the STXBP2 protein deficiency means this process cannot occur efficiently.

TITLE: Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells

Geneviève de Saint Basile
INSERM U768, Hôpital Necker, Paris, France.
Phone: 33-1-44-49-50-80; Fax: 33-1-42-73-06-40; E-mail: genevieve.de-saint-basile@inserm.fr.

View this article at: http://www.jci.org/articles/view/40732?key=HIH915i5gkk549w2m55m

MUSCLE BIOLOGY: Modifying muscular dystrophy

TITLE: Latent TGF-beta-binding protein 4 modifies muscular dystrophy in mice

Elizabeth M. McNally
University of Chicago, Chicago, Illinois, USA.
Phone: (773) 702-2672; Fax: (773) 702-2681; E-mail: emcnally@uchicago.edu.

View this article at: http://www.jci.org/articles/view/39845?key=Rs24GNdDJB9FEgtUGtU0

ONCOLOGY: Space invader: the protein Bmi-1 makes cells mobile and invasive

TITLE: The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells

Mu-Sheng Zeng
Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
Phone: 86-20-8734-3191; Fax: 86-20-8734-3171; E-mail: zengmsh@mail.sysu.edu.cn.

View this article at: http://www.jci.org/articles/view/39374?key=J3PO2o3oFtnMtgIWS5cT

GASTROENTEROLOGY: How nervous system defects can make the intestines seem blocked

TITLE: Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction

Lionel Larue
Institut Curie, Orsay, France.
Phone: 33-1-69-86-71-07; Fax: 33-1-69-86-71-09; E-mail: lionel.larue@curie.fr.

View this article at: http://www.jci.org/articles/view/39929?key=9UTP7XD4s2E2c3VetpFJ

PULMONARY: Mfge8 protein: a negative regulator of fibrosis

TITLE: Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages

Dean Sheppard
University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 514-4269; Fax: (415) 514-4278; E-mail: Dean.Sheppard@UCSF.edu.

View this article at: http://www.jci.org/articles/view/40053?key=HLojpM2Zb1i77pN9Dwz0

PHYSIOLOGY: Staying alive: progenitor cell survival requires the protein HuR

TITLE: Essential role of the RNA-binding protein HuR in progenitor cell survival in mice

Timothy Hla
Weill Cornell Medical College, New York, New York, USA.
Phone: (212) 746-9953; Fax: (212) 746-2830; E-mail: tih2002@med.cornell.edu

Hector Leonardo Aguila v
University of Connecticut Health Center, Farmington, Connecticut, USA.
Phone: (860) 679-7658; Fax: (860) 679-8130; E-mail: aguila@nso1.uchc.edu.

View this article at: http://www.jci.org/articles/view/38263?key=ag8txxvpr8yNlTd5o99I

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