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‘Forkhead’ gene expression balanced on a knife-edge
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TRENDS in Molecular Medicine Vol.7 No.2 February 2001
51
‘Forkhead’ gene expression balanced on a knife-edge Glaucoma is an extremely common degenerative blindness, some forms of which are caused by heritable abnormalities in the development of the anterior segments of the eye. The etiology of the changes in intra-ocular pressure, ganglion cell death and atrophy of the optic nerve that result in glaucoma is not well understood. Two recent papers might provide insight into the role of two members of the Forkhead family of genes, FOXC1 and FOXC2. Mutations in FOXC1 have been identified in individuals with autosomal dominant developmental abnormalities associated with glaucoma, including Axenfeld-Rieger anomoly and iris hypoplasia, and mice heterozygous for a targeted mutation of either Foxc1 or Foxc2 exhibit anterior segment abnormalities and develop glaucoma. Lehmann et al.1 identified a duplication of the region of chromosome 6p25 that contains FOXC1 in a large family with iris hypoplasia and glaucoma. These results suggest that parts of the developing eye are exquisitely sensitive to changes in the amount of the FOXC1 transcription factor. Further refinement of the extent of the duplicated region is needed to determine whether FOXC1 is the sole gene contributing to glaucoma in this family, but there are other families that show linkage to 6p25 but no FOXC1 mutations, and these are also good candidates for duplications. This is one of only three documented examples of a clinical
phenotype resulting from both the deletion and duplication of a single gene, the others being hereditary neuropathy with liability to pressure palsy (HNPP) and Charcot-Marie Tooth (CMT) Disease Type 1A. Based on the observations in mutant mice, it was presumed that FOXC2 mutations would also be found in some patients with glaucoma, although linkage has not been shown with chromosome 16q24 where FOXC2 is located, and FOXC2 mutations have not yet been described in glaucoma patients. Fang et al.2 have reported on the identification of FOXC2 mutations in a distinctly different disorder – hereditary Lymphedema–Distichiasis (LD) syndrome. The main features of LD are lymphedema (obstruction of lymphatic drainage), and distichiasis (the growth of an extra set of eyelashes). The mutation of FOXC2 in a disorder that does not include anterior segment abnormalities as part of its phenotype implies that the function of this transcription factor must differ from that of its mouse counterpart Foxc2, where mutations are known to cause eye abnormalities. This discrepancy in phenotype between species is a recapitulation of that seen in another form of heritable lymphedema which is caused by mutations in vascular endothelial growth factor receptor-3 (Vegfr-3), and is probably due to the difference in positional hydrostatic pressure between mice and humans. The horizontal stance of the mouse
may bypass any stress on the development of the lymphatic system caused by heterozygosity for Foxc2 or Vegfr-3, whereas the anatomy of humans may make this the primary system for abnormal development. On closer inspection, the mouse and human phenotypes may not be as vastly different as they appear. The defects in the heterozygous mice involve malformation of the ocular drainage system, a meshwork structure not dissimilar to the lymphatic system. Now that individuals with FOXC2 mutations have been identified, careful examination of their eyes would be a logical step, as would more detailed evaluation of the Foxc2 mutant mice for lymphatic abnormalities. It seems that there are yet more chapters to add to the FOXC story, and the plot is more complicated than initially predicted – study of these genes might eventually advance our understanding of both glaucoma and lymphedema. 1 Lehmann, O.J. et al. (2000) Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. Am. J. Hum. Genet. 67,1129–1135 2 Fang, J. et al. (2000) Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema–distichiasis syndrome. Am. J. Hum. Genet. 67,1382–1388
Lucy R. Osborne [email protected]
Gene therapy for neurodegeneration Glial cell derived neutrophic factor (GDNF) has been shown to protect a wide range of neurons – including dopaminergic and motor neurons – from degeneration and death. This potent neuroprotective effect of GDNF has made it a prime candidate for consideration as a treatment for Parkinson’s disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and also spinal cord injuries. The direct administration of GDNF to the brain has proven difficult, and so several groups have recently attempted to deliver and express GDNF using adenovirus and adenoassociated viral vectors. Though these studies have shown successful gene transfer, and in a number of different model systems evidence for neuroprotection, a recent study using an HIV-1 based lentiviral vector has shown the
most encouraging set of results to date1. In the study by Kordower et al., two primate models of Parkinson’s disease were used to assess the neuroprotective effect of GDNF. The lentiGDNF vector (or a control lentiviral vector expressing a marker gene) was administered by stererotaxic injection of the striatum and substantia nigra. In both models, lentiviral derived GDNF expression was detected by immunostaining in brain sections. Expression was not only localized around the injection site but there was also evidence of anterograde transport of GDNF protein. Improvements were measured in two neurological markers of Parkinson’s disease, and behavioral studies showed that monkeys who received lentiGDNF one week after Parkinson’s diseaseinducing neurotoxin treatment significantly
improved their performances in tests compared to control animals. No overt adverse effects associated with lentiviral administration were seen. Though substantial work is required before clinical trials can be considered, this study confirms that gene therapy using GDNF is a viable approach for the treatment of Parkinson’s disease, and potentially several other neurodegenerative diseases. 1 Kordower, J.H. et al. (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290, 767–773
Natasha Caplen [email protected]
http://tmm.trends.com 1471-4914/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
TRENDS in Molecular Medicine Vol.7 No.2 February 2001
51
‘Forkhead’ gene expression balanced on a knife-edge Glaucoma is an extremely common degenerative blindness, some forms of which are caused by heritable abnormalities in the development of the anterior segments of the eye. The etiology of the changes in intra-ocular pressure, ganglion cell death and atrophy of the optic nerve that result in glaucoma is not well understood. Two recent papers might provide insight into the role of two members of the Forkhead family of genes, FOXC1 and FOXC2. Mutations in FOXC1 have been identified in individuals with autosomal dominant developmental abnormalities associated with glaucoma, including Axenfeld-Rieger anomoly and iris hypoplasia, and mice heterozygous for a targeted mutation of either Foxc1 or Foxc2 exhibit anterior segment abnormalities and develop glaucoma. Lehmann et al.1 identified a duplication of the region of chromosome 6p25 that contains FOXC1 in a large family with iris hypoplasia and glaucoma. These results suggest that parts of the developing eye are exquisitely sensitive to changes in the amount of the FOXC1 transcription factor. Further refinement of the extent of the duplicated region is needed to determine whether FOXC1 is the sole gene contributing to glaucoma in this family, but there are other families that show linkage to 6p25 but no FOXC1 mutations, and these are also good candidates for duplications. This is one of only three documented examples of a clinical
phenotype resulting from both the deletion and duplication of a single gene, the others being hereditary neuropathy with liability to pressure palsy (HNPP) and Charcot-Marie Tooth (CMT) Disease Type 1A. Based on the observations in mutant mice, it was presumed that FOXC2 mutations would also be found in some patients with glaucoma, although linkage has not been shown with chromosome 16q24 where FOXC2 is located, and FOXC2 mutations have not yet been described in glaucoma patients. Fang et al.2 have reported on the identification of FOXC2 mutations in a distinctly different disorder – hereditary Lymphedema–Distichiasis (LD) syndrome. The main features of LD are lymphedema (obstruction of lymphatic drainage), and distichiasis (the growth of an extra set of eyelashes). The mutation of FOXC2 in a disorder that does not include anterior segment abnormalities as part of its phenotype implies that the function of this transcription factor must differ from that of its mouse counterpart Foxc2, where mutations are known to cause eye abnormalities. This discrepancy in phenotype between species is a recapitulation of that seen in another form of heritable lymphedema which is caused by mutations in vascular endothelial growth factor receptor-3 (Vegfr-3), and is probably due to the difference in positional hydrostatic pressure between mice and humans. The horizontal stance of the mouse
may bypass any stress on the development of the lymphatic system caused by heterozygosity for Foxc2 or Vegfr-3, whereas the anatomy of humans may make this the primary system for abnormal development. On closer inspection, the mouse and human phenotypes may not be as vastly different as they appear. The defects in the heterozygous mice involve malformation of the ocular drainage system, a meshwork structure not dissimilar to the lymphatic system. Now that individuals with FOXC2 mutations have been identified, careful examination of their eyes would be a logical step, as would more detailed evaluation of the Foxc2 mutant mice for lymphatic abnormalities. It seems that there are yet more chapters to add to the FOXC story, and the plot is more complicated than initially predicted – study of these genes might eventually advance our understanding of both glaucoma and lymphedema. 1 Lehmann, O.J. et al. (2000) Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. Am. J. Hum. Genet. 67,1129–1135 2 Fang, J. et al. (2000) Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema–distichiasis syndrome. Am. J. Hum. Genet. 67,1382–1388
Lucy R. Osborne [email protected]
Gene therapy for neurodegeneration Glial cell derived neutrophic factor (GDNF) has been shown to protect a wide range of neurons – including dopaminergic and motor neurons – from degeneration and death. This potent neuroprotective effect of GDNF has made it a prime candidate for consideration as a treatment for Parkinson’s disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and also spinal cord injuries. The direct administration of GDNF to the brain has proven difficult, and so several groups have recently attempted to deliver and express GDNF using adenovirus and adenoassociated viral vectors. Though these studies have shown successful gene transfer, and in a number of different model systems evidence for neuroprotection, a recent study using an HIV-1 based lentiviral vector has shown the
most encouraging set of results to date1. In the study by Kordower et al., two primate models of Parkinson’s disease were used to assess the neuroprotective effect of GDNF. The lentiGDNF vector (or a control lentiviral vector expressing a marker gene) was administered by stererotaxic injection of the striatum and substantia nigra. In both models, lentiviral derived GDNF expression was detected by immunostaining in brain sections. Expression was not only localized around the injection site but there was also evidence of anterograde transport of GDNF protein. Improvements were measured in two neurological markers of Parkinson’s disease, and behavioral studies showed that monkeys who received lentiGDNF one week after Parkinson’s diseaseinducing neurotoxin treatment significantly
improved their performances in tests compared to control animals. No overt adverse effects associated with lentiviral administration were seen. Though substantial work is required before clinical trials can be considered, this study confirms that gene therapy using GDNF is a viable approach for the treatment of Parkinson’s disease, and potentially several other neurodegenerative diseases. 1 Kordower, J.H. et al. (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290, 767–773
Natasha Caplen [email protected]
http://tmm.trends.com 1471-4914/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.