ARF6

Medical researchers have found a peptide which, when administered intravenously, homes in on the new blood vessels that are forming in damaged tissue. The peptide has been used as a delivery vehicle for therapeutics targeted at regenerating tissues. A new study has discovered that the peptide activates the natural healing mechanism in the tissue, accelerating regeneration. The finding opens new opportunities to treat not only skin wounds, but also any injuries resulting from accidents and traumas, such as ruptured muscles and fractured bones. Professor Tero Järvinen has found a peptide which, when administered intravenously, homes in on the new blood vessels that are forming in damaged tissue. The peptide has been used as a delivery vehicle for therapeutics targeted at regenerating tissues. A new study led by professor Järvinen discovered that the peptide activates the natural healing mechanism in the tissue, accelerating regeneration. The finding opens new opportunities to treat not only skin wounds, but also any injuries resulting from accidents and traumas, such as ruptured muscles and fractured bones. One of the key goals of medical science is to speed up the healing of tissue injuries in a way that would not enable the forming of less functional scar tissue in the affected areas. Professor Tero Järvinen at Tampere University in Finland is leading research that is seeking solutions to achieve this goal. In an earlier study, Järvinen discovered a so-called homing peptide, a small piece of protein that specifically seeks tissue damage via the bloodstream. The homing peptide was named the CAR peptide after its amino acid composition. It was screened out of more than a billion peptides using the screening technology of in vivo phage display. The peptide was used to transport a scar reducing drug to the wounds via systemic administration. Recently, the research group showed that the CAR transport peptide is itself a therapeutic drug. CAR activates a natural healing pathway crucial for tissue regeneration and accelerates wound healing without the need to attach to any kind of drug. The study, reported in a recent issue of Nature Communications, confirmed that the CAR peptide activates the tissue regeneration mechanism that is critical for wound healing by entering the wound through the bloodstream. In the wound, the peptide binds to syndecan-4, a cell membrane receptor. This binding activates the intracellular cytohesin-2 factor, which in turn activates the Arf6 GTPase that triggers cell migration, i.e., the migration of regenerating cells across the damaged area in the wound. By this molecular mechanism, the skin wounds in mice receiving the CAR peptide healed significantly faster than without the therapy. The ensuing scars were also smaller than without treatment. As this syndecan-4 dependent cell migration-mechanism is crucial for the healing of multiple injuries, such as skeletal muscle ruptures and bone fractures, the CAR peptide has multiple clinically relevant indications not just for traumatology, but also surgery and sports medicine. "Syndecan-4-dependent tissue regeneration is a key factor in the healing of several other tissue injuries beyond skin wounds, including muscle ruptures and bone fractures. The CAR peptide we found, which activates this natural healing mechanism, opens completely new possibilities for treating traumas and injuries not only in traumatology but also in surgery and sports injuries. Because the drug molecule actively seeks tissue damage through the bloodstream, the treated injury can be in any part of the body and can be targeted by the CAR peptide therapy," Järvinen explains. Professor Tero Järvinen led the study in cooperation with Academician of Science Erkki Ruoslahti. The research was carried out at Tampere University, Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA, USA) and at the University of California Santa Barbara (UCSB, CA, USA). Researchers from the University of Liverpool (UK) and the Wellcome Trust Centre for Cell-Matrix Research at the University of Manchester (UK) also participated.

Root hairs represent a low-cost strategy to enhance nutrient uptake because they can significantly increase the nutrient-acquiring surface of plant roots. While primary and lateral roots are stimulated to elongate when plants grow under mild nitrogen deficiency, the existence of such a foraging response for root hairs and its underlying regulatory mechanism remain elusive. Now, researchers have revealed a framework composed of specific molecular players meditating auxin synthesis, transport and signaling that triggers root hair elongation for nitrogen acquisition. Root hairs represent a low-cost strategy to enhance nutrient uptake because they can significantly increase the nutrient-acquiring surface of plant roots. While primary and lateral roots are stimulated to elongate when plants grow under mild nitrogen deficiency, the existence of such a foraging response for root hairs and its underlying regulatory mechanism remain elusive. Now, an international research team led by IPK Leibniz Institute revealed a framework composed of specific molecular players meditating auxin synthesis, transport and signaling that triggers root hair elongation for nitrogen acquisition. The results have been published in the journal Current Biology. Plants have evolved diverse adaptive strategies to optimize the exploration of light and soil resources from their environments. One of the most prominent adaptive responses is the developmental plasticity of their root systems, which enables plants to efficiently forage nutrient pools that fluctuate in space and time. As a crucial component determining the active root surface, root hairs represent a powerful morphological trait to improve water and nutrient acquisition. Root hairs are extensions of epidermal cells that effectively enlarge the root surface area and facilitate soil exploration for water and nutrients. Root hair development starts with cell fate specification, which determines whether an epidermal cell becomes a hair-forming cell (trichoblast) or a hairless cell (atrichoblast). "In our study, we first showed that nitrogen deficiency strongly stimulates root hair elongation in the model species Arabidopsis thaliana and that this response is crucial for plant fitness under low nitrogen," explains Prof. Dr. Nicolaus von Wirén, head of the department "Physiology and Cell Biology" at IPK Leibniz Institute. "And we then integrated transcriptomics, molecular genetics and cell biology approaches to establish that low nitrogen-induced root hair elongation builds on a spatially coordinated auxin signaling cascade that enters the root hair developmental program via the epidermal transcriptional module RHD6-LRL3." The signaling cascade consists of three stages. Through upregulation of the enzymes TAA1 and YUCCA8, low nitrogen increases auxin accumulation in the root apex (step 1, synthesis). Auxin is then directed shootward to the root hair differentiation zone via the transporters AUX1 and PIN2 (step 2, transport). Upon arrival, auxin activates the transcription factors ARF6 and ARF8 to promote the transcriptional module RHD6-LRL3, which is confined to the epidermis and steers root hair elongation in response to low nitrogen (step 3, signaling). "Overall, our results suggest that root hair elongation represents an additional systemically-induced foraging response strategy to explore the soil for nitrogen, gaining even more relevance as nitrogen deficiency becomes more severe," says Dr. Zhongtao Jia, first author of the study. "These findings add a new feature to our understanding of root foraging responses in low-nutrient environments and expand the mechanistic framework of hormone-regulated nutrient sensing in plant roots." Since more abundant and longer root hairs represent a low-cost strategy for plants to bring roots in contact with soil nutrients, understanding how root hair development is regulated by nitrogen provides new breeding targets for developing crops with enhanced nitrogen-uptake efficiency.