Loss of function of the homeobox gene Hoxa-9 perturbs early T-cell development and induces apoptosis in primitive thymocytes.
Hox homeobox genes play a crucial role in specifying the embryonic body pattern. However, a role for Hox genes in T-cell development has not been explored. The Hoxa-9 gene is expressed in normal adult and fetal thymuses. Fetal thymuses of mice homozygous for an interruption of the Hoxa-9 gene are one eighth normal size and have a 25-fold decrease in the number of primitive thymocytes expressing the interleukin-2 receptor (IL-2R, CD25). Progression to the double positive (CD4+CD8+) stage is dramatically retarded in fetal thymic organ cultures. This aberrant development is associated with decreased amounts of intracellular CD3 and T-cell receptor beta (TCRbeta) and reduced surface expression of IL-7R and E-cadherin. Mutant thymocytes show a significant increase in apoptotic cell death and premature downregulation of bcl-2 expression. A similar phenotype is seen in primitive thymocytes from adult Hoxa-9-/- mice and from mice transplanted with Hoxa-9-/- marrow. Hoxa-9 appears to play a previously unsuspected role in T-cell ontogeny by modulating cell survival of early thymocytes and by regulating their subsequent differentiation.
Izon
D J
DJ
Department of Medicine, Veterans Affairs Medical Center, University of California, San Francisco, CA 94121, USA.
Rozenfeld
S
S
Fong
S T
ST
Kömüves
L
L
Largman
C
C
Lawrence
H J
HJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000473:pathology*; D013950:Thymus Gland / Q000196:embryology / Q000473:pathology
D018398:Homeodomain Proteins; C097899:homeobox protein HOXA9