JCI online early table of contents: Oct. 3, 2011

A team of researchers led by Clifford Woolf and Chi Ma, at Children's Hospital Boston and Harvard Medical School, Boston, has identified a way to accelerate the regeneration of injured peripheral nerves in mice such that muscle function is restored. In an accompanying commentary, Ahmet Höke, at Johns Hopkins School of Medicine, Baltimore, discusses the importance of this work to the clinical problem.

Our peripheral nerves connect our brain and spinal cord to the rest of our body, controlling all volitional muscle movements. However, they are fragile and very easily damaged. Peripheral nerves can regenerate after injury, and if the site of damage is close to the muscle controlled by the damaged nerve, full muscle function is frequently restored. However, if the site of damage is far from the muscle controlled by the damaged nerve, recovery of muscle function is minimal. Woolf, Ma, and colleagues found that injured peripheral nerves grew faster in mice that overexpressed human heat shock protein 27 (Hsp27) than in normal mice. This enabled the peripheral nerves to form functional connections with their target muscle and led to recovery of muscle function. Clinical data are also provided to support the authors' suggestion that their work indicates that strategies that increase the rate of nerve growth may enhance functional recovery in patients after peripheral nerve damage.

TITLE: Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice

AUTHOR CONTACT:

Clifford J. Woolf
Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.919.2265; Fax: 617.919.2772; E-mail: clifford.woolf@childrens.harvard.edu.

Chi Him Eddie Ma
City University of Hong Kong, Hong Kong.
Phone: 852.3442.9328; Fax: 852.3442.0522; E-mail: eddiema@cityu.edu.hk.

View this article at: http://www.jci.org/articles/view/58675?key=0f90348dc02c50fde505

ACCOMPANYING COMMENTARY TITLE: A (heat) shock to the system promotes peripheral nerve regeneration

AUTHOR CONTACT:
Ahmet Höke
Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Phone: 410.955.2227; Fax: 410.502.5459; E-mail: ahoke@jhmi.edu.

View this article at: http://www.jci.org/articles/view/59320?key=1bd5a7d382c7a9cf5072

EDITOR'S PICK: Potential new treatment for stroke

Even though stroke is the third leading cause of death in the United States, there is only one approved treatment. Furthermore, fewer than 5% of stroke patients benefit from this treatment. New therapeutic targets are therefore urgently needed. Katrin Andreasson and colleagues, at Stanford University School of Medicine, Stanford, have now identified the protein EP4 as a potential new target for the treatment of stroke. Key to their suggestion that EP4 could provide therapeutic benefit to stroke patients, was the observation that therapeutic systemic administration of a selective EP4 agonist after stroke reduced brain damage and long-term behavioral deficits in mice.

TITLE: Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia

AUTHOR CONTACT:
Katrin Andreasson
Stanford University School of Medicine, Stanford, California, USA.
Phone: 650.723.1922; Fax: 650.498.6262; E-mail: kandreas@stanford.edu.

View this article at: http://www.jci.org/articles/view/46279?key=403ec32a48be38dd5d20

METABOLIC DISEASE: Antioxidants combat risk factor for type 2 diabetes in mice

The number of individuals with type 2 diabetes is reaching epidemic proportions. One of the main risk factors for developing type 2 diabetes is resistance of the cells in the body to the effects of the hormone insulin. Chu-Xia Deng and colleagues, at the National Institutes of Health, Bethesda, have now identified a new molecular pathway that helps mice remain sensitive to the effects of insulin. Disruption of this pathway in liver cells gradually led to whole-body insulin resistance in older mice that could largely be reversed by treatment with an antioxidant. Deng and colleagues therefore suggest that antioxidants might help protect older humans from progressive insulin resistance and thereby reduce their risk of developing type 2 diabetes.

TITLE: Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance

AUTHOR CONTACT:
Chu-Xia Deng
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.402.7225; Fax: 301.480.1135; E-mail: chuxiad@bdg10.niddk.nih.gov.

View this article at: http://www.jci.org/articles/view/46243?key=fc6b2e5a252217071ad1

Faciogenital dysplasia (FGDY; also known as Aarskog syndrome) is an inherited condition that is characterized predominantly by multiple skeletal defects. It is caused by mutations in the FGD1 gene, but how these mutations adversely affect skeletal development has remained an unanswered question. Work in mice by a team of researchers led by Laurie Glimcher, at Harvard School of Public Health, Boston, has now uncovered a potential answer to this question and identified a candidate therapeutic approach.

Initial analysis by Glimcher and colleagues determined that FGD1 activates a signaling pathway in bone cells called osteoblasts that involves the signaling protein MLK3. Further analysis revealed that MLK3 regulates the activity of the signaling proteins p38 MAPK and ERK, which in turn activate Runx2, the master regulator of osteoblast generation. The relevance of this signaling pathway to disease was highlighted by several observations, including the observation that FGDY-associated mutant forms of FGD1 were unable to activate MLK3 and that mice lacking MLK3 exhibited multiple skeletal defects that resembled those seen in individuals with FGDY. Glimcher and colleagues therefore suggest that modulating the signaling pathway they uncovered may benefit individuals with FGDY.

TITLE: MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice

AUTHOR CONTACT:
Laurie H. Glimcher
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: 617.432.0622; Fax: 617.432.1223; E-mail: lglimche@hsph.harvard.edu.

View this article at: http://www.jci.org/articles/view/59041?key=6dbe7896689116a61c2e

In individuals with colorectal, breast, and endometrial cancers, expression of the protein SCRIB is often mislocalized and deregulated. A team of researchers led by Patrick Humbert, at the Peter MacCallum Cancer Centre, Australia, has now identified a role for SCRIB in suppressing prostate tumor formation in mice. The clinical relevance of these data was highlighted by the finding that mislocalization of SCRIB is associated with poor survival in individuals with prostate cancer. Humbert and colleagues therefore suggest that the molecular mechanisms and cellular functions regulated by SCRIB could provide targets for anticancer therapeutics.

TITLE: SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

AUTHOR CONTACT:
Patrick O. Humbert
Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Phone: 61.0.3.96563526; Fax: 61.0.3.96561411; E-mail: Patrick.Humbert@petermac.org.

View this article at: http://www.jci.org/articles/view/58509?key=969a53d902f57793f5d1

Hearing loss can be caused by genetic mutations. Mutations in the SLC26A4 gene are a common cause of hearing loss associated with enlargement of the vestibular aqueducts (bony canals that travel from the inner ear to deep inside the skull). If strategies to prevent or delay progressive hearing loss in children with SLC26A4 mutations are to be developed, greater understanding of the function of the protein templated by the SLC26A4 gene is needed. A team of researchers led by Andrew Griffith, at the National Institutes of Health, Rockville, has now provided new insight into this issue.

Griffith and colleagues generated mice in which expression of the Slc26a4 gene could be deleted at different times during gestation and postnatal life. They found that expression of the Slc26a4 gene from day 16.5 of embryonic life through to the second day after birth was required for the acquisition of normal hearing. Eliminating expression of the Slc26a4 gene starting at day 18.5 of embryonic life recapitulated human hearing loss caused by SLC26A4 mutations. Griffith and colleagues hope that further analysis of their mice can provide additional mechanistic insight into hearing loss caused by SLC26A4 mutations that can be exploited for clinical benefit.

TITLE: Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition

AUTHOR CONTACT:
Andrew J. Griffith
National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, USA.
Phone: 301.402.2829; Fax: 301.402.7580; E-mail: griffita@nidcd.nih.gov.

View this article at: http://www.jci.org/articles/view/59353?key=7f9150d665469829f52f

Immune cells known as Tregs are key to preventing individuals from developing autoimmune diseases. They also prevent an individual's immune system from destroying "helpful" microbes that live on the skin and in the lungs and gut, and help restrain immune responses to dangerous invading microbes so that damage to surrounding tissue is limited. A team of researchers led by Yasmine Belkaid and Jinfang Zgu, at the National Institutes of Health, Bethesda, has now identified in mice a role for the gene regulatory protein GATA3 in controlling Treg physiology during inflammation. Specifically, the team found that expression of GATA3 by Tregs was required for them to be able to accumulate at sites of inflammation and to sustain high levels of expression of the protein Foxp3 (which is critical for their function) in various inflammatory settings. These data provide new insight into the molecular control of Treg function, further understanding of which is critical if these cells are to be harnessed for therapeutic benefit.

TITLE: GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice

AUTHOR CONTACT:

Yasmine Belkaid
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.451.8686; Fax: 301.451.8690; E-mail: YBelkaid@niaid.nih.gov.

Jinfang Zhu,
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.402.6662; Fax: 301.451.8690; E-mail: JFZHU@niaid.nih.gov.

View this article at: http://www.jci.org/articles/view/57456?key=c1bdd09c347d9c271ee3

Key to clearing the body of invading viruses is a population of immune cells known as CD8+ T cells. A team of researchers led by Christopher Love, at Massachusetts Institute of Technology, Cambridge, has now developed a high-throughout approach to concurrently assess multiple functions of individual human CD8+ T cells and used it to investigate the functions of individual CD8+ T cells from HIV-infected patients. The team found that upon seeing cells expressing HIV proteins, individual CD8+ T cells either killed the target cells or produced proinflammatory immune molecules, very few were able to both kill and produce proinflammatory immune molecules. Love and colleagues hope to use this approach to monitor the response of CD8+ T cells to candidate vaccines for HIV, something that they hope might help predict vaccine efficacy.

TITLE: A high-throughput single-cell analysis of human CD8+ T cell functions reveals discordance for cytokine secretion and cytolysis

AUTHOR CONTACT:
J. Christopher Love
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Phone: 617.324.2300; Fax: 617.258.5042; E-mail: clove@mit.edu.

View this article at: http://www.jci.org/articles/view/58653?key=abb9bd641e413ceb1b64

The liver, even in adults, has a remarkable ability to regenerate if damaged, for example by an invading virus. It also responds to chemicals that do not cause damage by increasing the number of cells it is composed of in order to rid the body of the chemical as fast as possible. A team of researchers, led by Joseph Locker, at Albert Einstein College of Medicine, New York, has now determined that induction of the protein Gadd45-beta is critical for the rapid expansion of liver mass that helps protect mice against chemical insults. These data provide new insight into the molecular control of the expansion of liver cell number following exposure to chemicals that do not actually cause liver damage.

TITLE: Gadd45-beta is an inducible coactivator of transcription that facilitates rapid liver growth in mice

AUTHOR CONTACT:
Joseph Locker
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718.430.3422; Fax: 718.430.3483; E-mail: joseph.locker@einstein.yu.edu.

View this article at: http://www.jci.org/articles/view/38760?key=644ded09fa0f4b548b51