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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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Placental dysmorphogenesis in the absence of laminin α5. (A and B) Immunostaining for laminin γ1 at E13.5 reveals the network of fetal blood vessel BLs in the placental labyrinth. The mutant vessels (B) are fewer, less branched, and wider bore than those in  the control (A). (C and D) Toluidine blue staining of E16.5 control (C) and mutant (D) labyrinth shows that large bore mutant vessels  (arrows in D) are still present at this later stage. The endothelium appears to have detached from the trophoblasts in these vessels. (E  and F) Transmission electron micrographs show definitively that some mutant fetal vessels (F) have become detached from the trophoblasts, leaving a cell-free space between the endothelium (e) and the trophoblasts (t), while in the control (E) the two cell layers remain  closely apposed. (G and H) Higher power micrographs of vascular BL. In control (G), both endothelium and trophoblast are tightly adherent to this BL, whereas in the mutant (H), the BL is patchy and has lost attachment to the trophoblasts. Bars: (in D) 100 μm for A  and B, 25 μm for C and D; (in F) 1 μm for E and F; (in H) 0.25 μm for G and H.
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Figure 8: Placental dysmorphogenesis in the absence of laminin α5. (A and B) Immunostaining for laminin γ1 at E13.5 reveals the network of fetal blood vessel BLs in the placental labyrinth. The mutant vessels (B) are fewer, less branched, and wider bore than those in the control (A). (C and D) Toluidine blue staining of E16.5 control (C) and mutant (D) labyrinth shows that large bore mutant vessels (arrows in D) are still present at this later stage. The endothelium appears to have detached from the trophoblasts in these vessels. (E and F) Transmission electron micrographs show definitively that some mutant fetal vessels (F) have become detached from the trophoblasts, leaving a cell-free space between the endothelium (e) and the trophoblasts (t), while in the control (E) the two cell layers remain closely apposed. (G and H) Higher power micrographs of vascular BL. In control (G), both endothelium and trophoblast are tightly adherent to this BL, whereas in the mutant (H), the BL is patchy and has lost attachment to the trophoblasts. Bars: (in D) 100 μm for A and B, 25 μm for C and D; (in F) 1 μm for E and F; (in H) 0.25 μm for G and H.

Mentions: The placental labyrinth was significantly smaller in mutants than controls by E13.5 and remained smaller at later ages (data not shown). Immunostaining with antibodies to laminin γ1 (to localize BLs) and to PECAM (to localize endothelial cells) revealed that the network of fetal blood vessels was present and associated with BLs in the mutants at E13.5. However, the complexity of vessel branching was markedly reduced in mutant homozygotes, and the diameter of the vessels was significantly increased (Fig. 8, A and B). This defect was still apparent at E16.5, indicating that branching of the blood vessels was not merely developmentally delayed. The resulting simplification of the labyrinth reduces the surface area available for exchange of molecules between the fetal and maternal bloodstreams, and could thereby lead to placental insufficiency in mutants. Consistent with this possibility, mutant embryos were almost always smaller than their normal littermates after E14.


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)

Placental dysmorphogenesis in the absence of laminin α5. (A and B) Immunostaining for laminin γ1 at E13.5 reveals the network of fetal blood vessel BLs in the placental labyrinth. The mutant vessels (B) are fewer, less branched, and wider bore than those in  the control (A). (C and D) Toluidine blue staining of E16.5 control (C) and mutant (D) labyrinth shows that large bore mutant vessels  (arrows in D) are still present at this later stage. The endothelium appears to have detached from the trophoblasts in these vessels. (E  and F) Transmission electron micrographs show definitively that some mutant fetal vessels (F) have become detached from the trophoblasts, leaving a cell-free space between the endothelium (e) and the trophoblasts (t), while in the control (E) the two cell layers remain  closely apposed. (G and H) Higher power micrographs of vascular BL. In control (G), both endothelium and trophoblast are tightly adherent to this BL, whereas in the mutant (H), the BL is patchy and has lost attachment to the trophoblasts. Bars: (in D) 100 μm for A  and B, 25 μm for C and D; (in F) 1 μm for E and F; (in H) 0.25 μm for G and H.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2132973&req=5

Figure 8: Placental dysmorphogenesis in the absence of laminin α5. (A and B) Immunostaining for laminin γ1 at E13.5 reveals the network of fetal blood vessel BLs in the placental labyrinth. The mutant vessels (B) are fewer, less branched, and wider bore than those in the control (A). (C and D) Toluidine blue staining of E16.5 control (C) and mutant (D) labyrinth shows that large bore mutant vessels (arrows in D) are still present at this later stage. The endothelium appears to have detached from the trophoblasts in these vessels. (E and F) Transmission electron micrographs show definitively that some mutant fetal vessels (F) have become detached from the trophoblasts, leaving a cell-free space between the endothelium (e) and the trophoblasts (t), while in the control (E) the two cell layers remain closely apposed. (G and H) Higher power micrographs of vascular BL. In control (G), both endothelium and trophoblast are tightly adherent to this BL, whereas in the mutant (H), the BL is patchy and has lost attachment to the trophoblasts. Bars: (in D) 100 μm for A and B, 25 μm for C and D; (in F) 1 μm for E and F; (in H) 0.25 μm for G and H.
Mentions: The placental labyrinth was significantly smaller in mutants than controls by E13.5 and remained smaller at later ages (data not shown). Immunostaining with antibodies to laminin γ1 (to localize BLs) and to PECAM (to localize endothelial cells) revealed that the network of fetal blood vessels was present and associated with BLs in the mutants at E13.5. However, the complexity of vessel branching was markedly reduced in mutant homozygotes, and the diameter of the vessels was significantly increased (Fig. 8, A and B). This defect was still apparent at E16.5, indicating that branching of the blood vessels was not merely developmentally delayed. The resulting simplification of the labyrinth reduces the surface area available for exchange of molecules between the fetal and maternal bloodstreams, and could thereby lead to placental insufficiency in mutants. Consistent with this possibility, mutant embryos were almost always smaller than their normal littermates after E14.

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