Abstract
In previous in vitro studies, we proposed a role for the extracellular matrix component, laminin- 2, and its integrin receptor, VLA-6, in thymocyte development. The characterization of two dystrophic mouse strains with different defects in laminin-2 allowed us to examine this proposal in vivo. Mice deficient in laminin-2, dy/dy, show a significant reduction in thymus size and number of thymocytes compared to normal littermates. These mice also exhibited apparent alterations of thymic architecture. Examination of the CD4/CD8 populations in dy/dy thymi showed large relative increases in the DN (CD4-CD8-) and SP (CD4+CD8-, CD4-CD8+) populations and a significant decrease in the DP (CD4+CD8+) population. Further examination of the DN population for CD44 and CD25 expression showed a remarkable decrease in the more mature pre-T cell populations. Analysis of apoptosis in situ, and by flow cytometry, in dy/dy thymi revealed a significant increase in apoptotic DN thymocytes in the capsule and subcapsular regions. Interestingly, thymocyte development appeared to proceed normally in dystrophic mice expressing a mutant form of laminin-2, dy2J, as well as, in fetal and neonatal dy/dy mice. We propose that laminin-2 plays an active role in thymocyte development by delivering cell survival and differentiation signals at specific stages of development in young adult mice.
Highlights
The laminins are a family of extracellular matrix (ECM) proteins found in basement membranes; they are heterotrimeric proteins consisting of a heavy chain (c) and two light chains (13, T)
Thymus weight alnd the number of thymocytes recovered from each thymus are standardized to body mass and thymus mass respectively to demonstrate that the thymus is reduced in size and cell numbers even relative to the reduced body size of these mice, i.e. the loss of thymocytes is out of proportion with the size of the mice
We previously showed that laminin-2, and not laminn-1, is expressed in the thymus and that a portion of thymocytes can adhere to laminin-2 (Chang et al, 1993)
Summary
The laminins are a family of extracellular matrix (ECM) proteins found in basement membranes; they are heterotrimeric proteins consisting of a heavy chain (c) and two light chains (13, T). Laminin-1 (classically known as laminin) is composed of the 1, [1 and T1 chains while laminin-2 (merosin) contains the cz2, [31 and y1 chains (Wewer and Engvall 1994, Burgeson et al, 1994). Laminin-2 has been shown to be a ligand for VLA-6 (cZ6l), an integrin which is expressed on thymocytes (Chang et al, 1993, Lannes-Vieira et al, 1993). The various laminin isoforms are expressed in a tissue or developmental. Ph.D., NIH/NIAID, Twinbrook II, Rm. 205, 12441 Parklawn Dr Rockville, MD 20852-1727. Voice 301-496-8247, FAX 301-480-9094, jcoligan @ niaid.nih.gov stage- specific manner (Leivo and Engvall, 1988, Ehrig et al, 1990, Wewer et al, 1994) Ph.D., NIH/NIAID, Twinbrook II, Rm. 205, 12441 Parklawn Dr Rockville, MD 20852-1727. voice 301-496-8247, FAX 301-480-9094, jcoligan @ niaid.nih.gov stage- specific manner (Leivo and Engvall, 1988, Ehrig et al, 1990, Wewer et al, 1994)
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