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Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain.

Miner JH, Cunningham J, Sanes JR - J. Cell Biol. (1998)

Bottom Line: Previously described mutations in laminin chain genes result in diverse disorders that are manifested postnatally and therefore provide little insight into laminin's roles in embryonic development.Other laminin alpha chains accumulate in these BLs, but this compensation is apparently functionally inadequate.Our results identify new roles for laminins and BLs in diverse developmental processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Renal Division, St. Louis, Missouri, USA.

ABSTRACT
Laminins are the major noncollagenous glycoproteins of all basal laminae (BLs). They are alpha/beta/gamma heterotrimers assembled from 10 known chains, and they subserve both structural and signaling roles. Previously described mutations in laminin chain genes result in diverse disorders that are manifested postnatally and therefore provide little insight into laminin's roles in embryonic development. Here, we show that the laminin alpha5 chain is required during embryogenesis. The alpha5 chain is present in virtually all BLs of early somite stage embryos and then becomes restricted to specific BLs as development proceeds, including those of the surface ectoderm and placental vasculature. BLs that lose alpha5 retain or acquire other alpha chains. Embryos lacking laminin alpha5 die late in embryogenesis. They exhibit multiple developmental defects, including failure of anterior neural tube closure (exencephaly), failure of digit septation (syndactyly), and dysmorphogenesis of the placental labyrinth. These defects are all attributable to defects in BLs that are alpha5 positive in controls and that appear ultrastructurally abnormal in its absence. Other laminin alpha chains accumulate in these BLs, but this compensation is apparently functionally inadequate. Our results identify new roles for laminins and BLs in diverse developmental processes.

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Molecular compensation for loss of laminin α5 in  Lama5 −/− ectoderm. E13.5 controls (A–E) and mutants (F–J)  were stained with antisera specific for the five known laminin α  chains. Micrographs show surface ectoderm from the flank. Normal ectodermal BL (arrowheads) contained only α3 and α5 at  this age, but mutant BL contained the α1–α4 chains. Thus, α1, α2,  and α4 were upregulated in response to loss of α5. Bar, 50 μm.
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Figure 7: Molecular compensation for loss of laminin α5 in Lama5 −/− ectoderm. E13.5 controls (A–E) and mutants (F–J) were stained with antisera specific for the five known laminin α chains. Micrographs show surface ectoderm from the flank. Normal ectodermal BL (arrowheads) contained only α3 and α5 at this age, but mutant BL contained the α1–α4 chains. Thus, α1, α2, and α4 were upregulated in response to loss of α5. Bar, 50 μm.

Mentions: In some laminin mutants, loss of one chain results in compensatory upregulation of other chains. For example, laminin β1 is found ectopically in the mature glomerular basement membrane in kidneys of mice with a targeted mutation in the laminin β2 chain gene. This compensatory response produces a structurally intact BL that nevertheless does not function properly as a filter (Noakes et al., 1995b). Likewise, loss of laminin α2 in dy/dy mice results in upregulation of α4, which is, however, insufficient to prevent muscular dystrophy (Patton et al., 1997). In view of these precedents, we assessed the consequences of laminin α5 deficiency on the composition of ectodermal BL. In control embryos, α3, α5, and γ1 were present in ectodermal BL at E13.5, but α1, α2, and α4 were undetectable (Fig. 7, A–E). In mutants, the entire surface ectoderm was coated by a laminin γ1–positive BL, consistent with electron microscopic observations that the discontinuities in this structure were small and sparse (data not shown), except at the particular sites discussed above. The α5 chain was absent, as expected, but the α3 chain was retained at apparently normal levels. In addition, the α1, α2, and α4 chains were present in many but not all segments of mutant ectodermal BL (Fig. 7, F–J, and data not shown). Thus, absence of laminin α5 led to retention and/or ectopic accumulation of the α1, α2, and α4 chains. The preservation of the mutant BL may result from the retention of α3-containing laminins or the ectopic accumulation of α1-, α2-, and α4-containing laminins. Conversely, the localized defects in mutant BL that lead to exencephaly and syndactyly may reflect either regional differences in the extent of compensation or uniform weakness that renders the BL vulnerable in regions subjected to greatest stress.


Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain.

Miner JH, Cunningham J, Sanes JR - J. Cell Biol. (1998)

Molecular compensation for loss of laminin α5 in  Lama5 −/− ectoderm. E13.5 controls (A–E) and mutants (F–J)  were stained with antisera specific for the five known laminin α  chains. Micrographs show surface ectoderm from the flank. Normal ectodermal BL (arrowheads) contained only α3 and α5 at  this age, but mutant BL contained the α1–α4 chains. Thus, α1, α2,  and α4 were upregulated in response to loss of α5. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2132973&req=5

Figure 7: Molecular compensation for loss of laminin α5 in Lama5 −/− ectoderm. E13.5 controls (A–E) and mutants (F–J) were stained with antisera specific for the five known laminin α chains. Micrographs show surface ectoderm from the flank. Normal ectodermal BL (arrowheads) contained only α3 and α5 at this age, but mutant BL contained the α1–α4 chains. Thus, α1, α2, and α4 were upregulated in response to loss of α5. Bar, 50 μm.
Mentions: In some laminin mutants, loss of one chain results in compensatory upregulation of other chains. For example, laminin β1 is found ectopically in the mature glomerular basement membrane in kidneys of mice with a targeted mutation in the laminin β2 chain gene. This compensatory response produces a structurally intact BL that nevertheless does not function properly as a filter (Noakes et al., 1995b). Likewise, loss of laminin α2 in dy/dy mice results in upregulation of α4, which is, however, insufficient to prevent muscular dystrophy (Patton et al., 1997). In view of these precedents, we assessed the consequences of laminin α5 deficiency on the composition of ectodermal BL. In control embryos, α3, α5, and γ1 were present in ectodermal BL at E13.5, but α1, α2, and α4 were undetectable (Fig. 7, A–E). In mutants, the entire surface ectoderm was coated by a laminin γ1–positive BL, consistent with electron microscopic observations that the discontinuities in this structure were small and sparse (data not shown), except at the particular sites discussed above. The α5 chain was absent, as expected, but the α3 chain was retained at apparently normal levels. In addition, the α1, α2, and α4 chains were present in many but not all segments of mutant ectodermal BL (Fig. 7, F–J, and data not shown). Thus, absence of laminin α5 led to retention and/or ectopic accumulation of the α1, α2, and α4 chains. The preservation of the mutant BL may result from the retention of α3-containing laminins or the ectopic accumulation of α1-, α2-, and α4-containing laminins. Conversely, the localized defects in mutant BL that lead to exencephaly and syndactyly may reflect either regional differences in the extent of compensation or uniform weakness that renders the BL vulnerable in regions subjected to greatest stress.

Bottom Line: Previously described mutations in laminin chain genes result in diverse disorders that are manifested postnatally and therefore provide little insight into laminin's roles in embryonic development.Other laminin alpha chains accumulate in these BLs, but this compensation is apparently functionally inadequate.Our results identify new roles for laminins and BLs in diverse developmental processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Renal Division, St. Louis, Missouri, USA.

ABSTRACT
Laminins are the major noncollagenous glycoproteins of all basal laminae (BLs). They are alpha/beta/gamma heterotrimers assembled from 10 known chains, and they subserve both structural and signaling roles. Previously described mutations in laminin chain genes result in diverse disorders that are manifested postnatally and therefore provide little insight into laminin's roles in embryonic development. Here, we show that the laminin alpha5 chain is required during embryogenesis. The alpha5 chain is present in virtually all BLs of early somite stage embryos and then becomes restricted to specific BLs as development proceeds, including those of the surface ectoderm and placental vasculature. BLs that lose alpha5 retain or acquire other alpha chains. Embryos lacking laminin alpha5 die late in embryogenesis. They exhibit multiple developmental defects, including failure of anterior neural tube closure (exencephaly), failure of digit septation (syndactyly), and dysmorphogenesis of the placental labyrinth. These defects are all attributable to defects in BLs that are alpha5 positive in controls and that appear ultrastructurally abnormal in its absence. Other laminin alpha chains accumulate in these BLs, but this compensation is apparently functionally inadequate. Our results identify new roles for laminins and BLs in diverse developmental processes.

Show MeSH
Related in: MedlinePlus