A new therapeutic target in iron overload disorders

Iron is required for multiple cellular functions, including the synthesis of hemoglobin, but a buildup of excess cellular iron can be toxic. Hepcidin is a circulating molecule produced by the liver that triggers the degradation of iron transporters in the intestine and certain immune cells. In response to rising iron stores, increased hepcidin levels lead to reduced iron absorption from the diet. Iron overload can occur due to inherited mutations in this iron homeostasis pathway, or to disorders that lead to ineffective blood cell development, such as β-thalassemia.

In this issue of the Journal of Clinical Investigation, Shuling Guo, Carla Casu and colleagues at Weill Cornell Medical College in New York increased hepcidin levels by generating molecules that target a negative regulator of hepcidin production called TMPRSS6. Injection of these molecules improved iron homeostasis and blood cell development in mouse models of iron overload. In the accompanying commentary, Karin Finberg of Duke University how these findings could impact the treatment of patients with β-thalassemia.

TITLE: Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice
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ACCOMPANYING ARTICLE TITLE: Striking the target in iron overload disorders
View this article at: http://www.jci.org/articles/view/68889?key=c5c95c5b3a8b1b1152ed

Protein pair promotes skin regeneration

Because skin protects our bodies from pathogens and harsh environmental conditions, it must undego constant renewal. The cells that form the top most layer of the skin, known as cornified keratinocytes, are shed constantly and must be resupplied. Repression of a cellular signaling pathway mediated by ERK proteins is required for differentiation of keratinocytes, but this pathway is hyperactivated in a group of disorders known as RASopathies.

In this issue of the Journal of Clinical Investigation, researchers led by Kathleen Green at Northwestern University, identified a pair of proteins that function to suppress ERK activation and drive the development of keratinocytes. In skin cells, two proteins, RAS and SHOC2 form a complex that activates ERK. Green and colleagues found that the proteins Erbin and DSG1 disrupt SHOC2/RAS complexes and prevent ERK activation. These findings reveal a previously unknown role for DSG1/Erbin in skin disorders. In a companion commentary, John Stanley of the University of Pennsylvania discusses how these findings contribute to our understanding of how skin is maintained.

TITLE: Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation
View this article at: http://www.jci.org/articles/view/65220?key=e01448d06d00a554dcf9

ACCOMPANYING COMMENTARY TITLE: Desmoglein 1, Differentiation, and Disease
View this article at: http://www.jci.org/articles/view/69071?key=64cb3a0ec3a2a8bbeb4f

Researchers optimize embryonic stem cell-derived retinal progenitors for transplant

Tissues derived from embryonic stem cells (ESCs) could potentially be used to replace cells and tissues in patients with degenerative diseases, but they could also cause serious side effects - ESCs and ESC-derived progenitor cells have previously been shown to spontaneously form tumors.

In this issue of the Journal of Clinical Investigation, researchers led by Ying Jin at the Institute of Health Sciences in Shanghai, identified a cellular signaling pathway that controls tumorigenicity in ESC-derived retinal progenitor cells. Retinal degeneration is a leading cause of blindness that could potentially be treated by replacement of the defective retinal cells. Jin and colleagues found that the WNT signaling cascade was a critical determinant of both the tumorigenicity and therapeutic function of ESC-derived retinal progenitors. By inhibiting WNT signaling, they could improve the function of retinal progenitors in mice while preventing tumor formation. In a companion commentary, Kang Zhang and colleagues the University of California, San Diego, discuss how these findings could broadly apply to the development of new stem cell therapies.

TITLE: WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors
View this article at: http://www.jci.org/articles/view/65048?key=7aa034c46aa441cf9fbe

ACCOMPANYING COMMENTARY: Wnt signaling in stem cell differentiation and tumor formation
View this article at: http://www.jci.org/articles/view/69324?key=6f41b86a23b1a3729ecd