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Gun shots heal skin wounds
Literature
The
MOLECULAR MEDICINE TODAY, JUNE 1999 (VOL. 5)
Gun shots heal skin wounds
Cochlear development and the search for deafness genes About half the cases of deafness result from single gene defects. Many affected families are small and genetic mapping of the causative loci identify large regions with hundreds of potential candidate genes. These intervals cannot be narrowed down through observed recombinations as too few meiotic events are available in small families. As testing positional candidates is laborious and time-consuming, the genes that cause non-syndromic hearing loss have only been identified in ten of .40 such mapped loci. Because all the genes that have already been identified to cause hearing disorders are expressed in the cochlea, Skvorak et al.1 decided to construct a cDNA library from human cochlea to generate expressed sequence tags (ESTs). The cochlear ESTs were analyzed for sequence homology to known genes and other ESTs, and many were mapped to chromosomal regions. A total of 4194 ESTs were created and several corresponded to known hearing disorder genes, many were mapped to candidate regions for other hearing impairment loci, some showed homology to genes in other species, and others had no homology to known sequences. The 57 ESTs that map to regions for 18 non-syndromic hearing loss loci and four Usher syndrome subtypes will be of particular interest to gene hunters. Another source of candidate disease-causing genes is an animal model that has the relevant clinical features. The delicate and regular arrangement of hair cells and supporting cells in the mammalian cochlea is critical to normal hearing. Lanford et al.2 show that the Notch signalling pathway plays a role in lateral inhibition and the regular spacing of these cells in the mammalian cochlear membrane. In situ hybridization to mouse embryo tissue sections showed that, in the developing mouse, the prog-
238
False-colour scanning electron micrograph of the organ of Corti, showing the precise arrangement of the three rows of outer hair cells and one row of inner hair cells. Kindly provided by Dr David N. Furness and Professor Carole Hackney, Mackay Institute for Communication and Neuroscience, Keele University, UK.
enitor cells of the sensory cochlear membrane all produce the Notch1 receptor protein and have the ability to develop into hair cells. Prior to the differentiation of the sensory hair cells, some of the cells downregulate Notch1 expression and produce the Jagged2 protein, which binds to the Notch1 receptors on the neighboring cells, thereby inhibiting their development into hair cells. Further support for the involvement of Jagged2 in lateral inhibition was obtained by creating homozygous Jag2 knockout mice in which sensory hair cells were over produced. The intriguing question as to why sensory hair cell progenitors downregulate Notch1 and express Jag2 remains to be answered. Tissue-specific EST collections and genes with related functions in other organisms provide rich and valuable candidate gene resources for human disease. The cochlear EST database will be eagerly scrutinized by scientists working on deafness and will undoubtedly speed gene discovery and a better understanding of hearing impairment. 1 Skvorak, A.B. et al. (1999) Human cochlear expressed sequence tags provide insight into cochlear gene expression and identify candidate genes for deafness, Hum. Mol. Genet. 8, 439Ð452 2 Lanford, P.J. et al. (1999) Notch signalling pathway mediates hair cell development in mammalian cochlea, Nat. Genet. 21, 289Ð292 Mich•le Ramsay PhD [email protected]
Many approaches have been used to express therapeutic genes in skin-cell populations, including the use of so-called Ôgene-gunsÕ. This name has been applied to a variety of devices that have been designed to shoot particles coated with DNA into the skin. Perhaps perversely, Eming et al.1 have used this ÔbiolisticÕ approach to improve wound healing in rat skin. Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymally derived cells and upregulates the expression of genes that encode fibronectin and procollagen type 1 in fibroblasts. The authors reasoned that delivery of DNA that encodes PDGF to skin wounds should therefore enhance the wound-healing process. The success of healing can be measured by an increase in the tensile strength of the wound Ð its resistance to being broken open again once healed. The authors found that different isoforms of PDGF all increased the tensile strength of wounds at both seven and 14 days after shooting. As human transgenes were used, the authors were able to demonstrate that gene expression was detectable up to three days but not after five. Thus, transgene expression for only a short period was able to improve wound healing after 14 days. Of course, if wounds heal too strongly, scarring might result, and so more work is needed in animal models before this treatment could be applied to human wounds. 1 Eming, S.A. et al. (1999) Particle-mediated gene transfer of PDGF isoforms promotes wound repair, J. Invest. Dermatol. 112, 297Ð302 Ian A. McKay MA, PhD [email protected]
The literature section is designed to alert readers to recent primary papers that are important to biomedical researchers, particularly innovative, likely to have significant clinical impact, or controversial. A panel of senior active researchers is commissioned to select one or two papers published in the last six weeks that is within their area of expertise. If you are interested in joining this panel, send an e-mail message to the Editor at: [email protected]
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.
The
MOLECULAR MEDICINE TODAY, JUNE 1999 (VOL. 5)
Gun shots heal skin wounds
Cochlear development and the search for deafness genes About half the cases of deafness result from single gene defects. Many affected families are small and genetic mapping of the causative loci identify large regions with hundreds of potential candidate genes. These intervals cannot be narrowed down through observed recombinations as too few meiotic events are available in small families. As testing positional candidates is laborious and time-consuming, the genes that cause non-syndromic hearing loss have only been identified in ten of .40 such mapped loci. Because all the genes that have already been identified to cause hearing disorders are expressed in the cochlea, Skvorak et al.1 decided to construct a cDNA library from human cochlea to generate expressed sequence tags (ESTs). The cochlear ESTs were analyzed for sequence homology to known genes and other ESTs, and many were mapped to chromosomal regions. A total of 4194 ESTs were created and several corresponded to known hearing disorder genes, many were mapped to candidate regions for other hearing impairment loci, some showed homology to genes in other species, and others had no homology to known sequences. The 57 ESTs that map to regions for 18 non-syndromic hearing loss loci and four Usher syndrome subtypes will be of particular interest to gene hunters. Another source of candidate disease-causing genes is an animal model that has the relevant clinical features. The delicate and regular arrangement of hair cells and supporting cells in the mammalian cochlea is critical to normal hearing. Lanford et al.2 show that the Notch signalling pathway plays a role in lateral inhibition and the regular spacing of these cells in the mammalian cochlear membrane. In situ hybridization to mouse embryo tissue sections showed that, in the developing mouse, the prog-
238
False-colour scanning electron micrograph of the organ of Corti, showing the precise arrangement of the three rows of outer hair cells and one row of inner hair cells. Kindly provided by Dr David N. Furness and Professor Carole Hackney, Mackay Institute for Communication and Neuroscience, Keele University, UK.
enitor cells of the sensory cochlear membrane all produce the Notch1 receptor protein and have the ability to develop into hair cells. Prior to the differentiation of the sensory hair cells, some of the cells downregulate Notch1 expression and produce the Jagged2 protein, which binds to the Notch1 receptors on the neighboring cells, thereby inhibiting their development into hair cells. Further support for the involvement of Jagged2 in lateral inhibition was obtained by creating homozygous Jag2 knockout mice in which sensory hair cells were over produced. The intriguing question as to why sensory hair cell progenitors downregulate Notch1 and express Jag2 remains to be answered. Tissue-specific EST collections and genes with related functions in other organisms provide rich and valuable candidate gene resources for human disease. The cochlear EST database will be eagerly scrutinized by scientists working on deafness and will undoubtedly speed gene discovery and a better understanding of hearing impairment. 1 Skvorak, A.B. et al. (1999) Human cochlear expressed sequence tags provide insight into cochlear gene expression and identify candidate genes for deafness, Hum. Mol. Genet. 8, 439Ð452 2 Lanford, P.J. et al. (1999) Notch signalling pathway mediates hair cell development in mammalian cochlea, Nat. Genet. 21, 289Ð292 Mich•le Ramsay PhD [email protected]
Many approaches have been used to express therapeutic genes in skin-cell populations, including the use of so-called Ôgene-gunsÕ. This name has been applied to a variety of devices that have been designed to shoot particles coated with DNA into the skin. Perhaps perversely, Eming et al.1 have used this ÔbiolisticÕ approach to improve wound healing in rat skin. Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymally derived cells and upregulates the expression of genes that encode fibronectin and procollagen type 1 in fibroblasts. The authors reasoned that delivery of DNA that encodes PDGF to skin wounds should therefore enhance the wound-healing process. The success of healing can be measured by an increase in the tensile strength of the wound Ð its resistance to being broken open again once healed. The authors found that different isoforms of PDGF all increased the tensile strength of wounds at both seven and 14 days after shooting. As human transgenes were used, the authors were able to demonstrate that gene expression was detectable up to three days but not after five. Thus, transgene expression for only a short period was able to improve wound healing after 14 days. Of course, if wounds heal too strongly, scarring might result, and so more work is needed in animal models before this treatment could be applied to human wounds. 1 Eming, S.A. et al. (1999) Particle-mediated gene transfer of PDGF isoforms promotes wound repair, J. Invest. Dermatol. 112, 297Ð302 Ian A. McKay MA, PhD [email protected]
The literature section is designed to alert readers to recent primary papers that are important to biomedical researchers, particularly innovative, likely to have significant clinical impact, or controversial. A panel of senior active researchers is commissioned to select one or two papers published in the last six weeks that is within their area of expertise. If you are interested in joining this panel, send an e-mail message to the Editor at: [email protected]
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.