Publikationsdatum:
2009-06-26
Beschreibung:
Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative. This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation. Both X-irradiation and thalidomide-induced phocomelia have been interpreted as patterning defects in the context of the progress zone model, which states that a cell's proximodistal identity is determined by the length of time spent in a distal limb region termed the 'progress zone'. Indeed, studies of X-irradiation-induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the progress zone model. Here, using a combination of molecular analysis and lineage tracing in chick, we show that X-irradiation-induced phocomelia is fundamentally not a patterning defect, but rather results from a time-dependent loss of skeletal progenitors. Because skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the aetiology lies not in a defect in the patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that proximodistal patterning is unaffected after X-irradiation does not support the predictions of the progress zone model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711994/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711994/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Galloway, Jenna L -- Delgado, Irene -- Ros, Maria A -- Tabin, Clifford J -- F32 HD057701/HD/NICHD NIH HHS/ -- F32 HD057701-01/HD/NICHD NIH HHS/ -- F32 HD057701-02/HD/NICHD NIH HHS/ -- F32HD057701/HD/NICHD NIH HHS/ -- L40 HD057084/HD/NICHD NIH HHS/ -- L40 HD057084-01/HD/NICHD NIH HHS/ -- R37 HD032443/HD/NICHD NIH HHS/ -- England -- Nature. 2009 Jul 16;460(7253):400-4. doi: 10.1038/nature08117. Epub 2009 Jun 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19553938" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Animals
;
Body Patterning/*radiation effects
;
Bone and Bones/cytology/radiation effects
;
Cell Death/radiation effects
;
Cell Differentiation/radiation effects
;
Cell Lineage/radiation effects
;
Cell Proliferation/radiation effects
;
Chick Embryo
;
Chondrogenesis/radiation effects
;
Ectromelia/*etiology/genetics/*pathology
;
Gene Expression Regulation, Developmental/radiation effects
;
Limb Buds/abnormalities/*pathology/*radiation effects/transplantation
;
Reproducibility of Results
;
Stem Cells/cytology/radiation effects
;
Thalidomide/adverse effects
;
Time Factors
;
X-Rays/adverse effects
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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