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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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Exencephaly in Lama5 −/− embryos. (A and B) Whole  mount views of control and mutant embryos at E13.5. Exencephalics lack the skin and skull that normally enclose the brain and  have a topologically “inside out” brain that does not develop  properly. The skin and skull of the control was dissected away to  allow direct comparison of mutant and normal brains. (C and D)  Immunohistochemical localization of proliferating cells with anti-BrdU and alkaline phosphatase chemistry after labeling for 1 h in  utero with BrdU. (C) In normal neural tissue (n), BrdU-labeled  cells (arrow) are confined to the ventricular zone. v, ventricle.  (D) In exencephalics, labeled cells (arrow) are found on the outer  surface of the neural tissue. This surface would have been ventricular had the neural tube closed, but now it is in direct contact  with amniotic fluid. Skin and skull (s) overlay the brain in the  control but are missing from the mutant. Pia is indicated by  dashed lines. (E and F) Toluidine blue–stained sections through  the anterior of E8.7 control and mutant embryos; the neural tube  is unclosed at this stage in both control and mutant. Electron micrographs shown in Fig. 6 were obtained from these regions.  Bars: (B) 1 mm; (D) 0.25 mm; (F) 0.2 mm.
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Figure 5: Exencephaly in Lama5 −/− embryos. (A and B) Whole mount views of control and mutant embryos at E13.5. Exencephalics lack the skin and skull that normally enclose the brain and have a topologically “inside out” brain that does not develop properly. The skin and skull of the control was dissected away to allow direct comparison of mutant and normal brains. (C and D) Immunohistochemical localization of proliferating cells with anti-BrdU and alkaline phosphatase chemistry after labeling for 1 h in utero with BrdU. (C) In normal neural tissue (n), BrdU-labeled cells (arrow) are confined to the ventricular zone. v, ventricle. (D) In exencephalics, labeled cells (arrow) are found on the outer surface of the neural tissue. This surface would have been ventricular had the neural tube closed, but now it is in direct contact with amniotic fluid. Skin and skull (s) overlay the brain in the control but are missing from the mutant. Pia is indicated by dashed lines. (E and F) Toluidine blue–stained sections through the anterior of E8.7 control and mutant embryos; the neural tube is unclosed at this stage in both control and mutant. Electron micrographs shown in Fig. 6 were obtained from these regions. Bars: (B) 1 mm; (D) 0.25 mm; (F) 0.2 mm.

Mentions: In ∼60% of Lama5 −/− fetuses examined, the brain was enlarged and misshapen, and it was not covered by skin or skull (Fig. 5, A and B); the remaining mutants appeared to have grossly normal heads (data not shown). This partially penetrant defect is termed exencephaly, a condition in which the cranial vault fails to develop, and the tissues of the brain are exposed (Wallace and Knights, 1978). We do not know why this defect is partially penetrant, but we do note that partial penetrance has been observed in other mutant strains that exhibit exencephaly (Wallace and Knights, 1978; Macdonald et al., 1989; Vogelweid et al., 1993; Harris and Juriloff, 1997).


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)

Exencephaly in Lama5 −/− embryos. (A and B) Whole  mount views of control and mutant embryos at E13.5. Exencephalics lack the skin and skull that normally enclose the brain and  have a topologically “inside out” brain that does not develop  properly. The skin and skull of the control was dissected away to  allow direct comparison of mutant and normal brains. (C and D)  Immunohistochemical localization of proliferating cells with anti-BrdU and alkaline phosphatase chemistry after labeling for 1 h in  utero with BrdU. (C) In normal neural tissue (n), BrdU-labeled  cells (arrow) are confined to the ventricular zone. v, ventricle.  (D) In exencephalics, labeled cells (arrow) are found on the outer  surface of the neural tissue. This surface would have been ventricular had the neural tube closed, but now it is in direct contact  with amniotic fluid. Skin and skull (s) overlay the brain in the  control but are missing from the mutant. Pia is indicated by  dashed lines. (E and F) Toluidine blue–stained sections through  the anterior of E8.7 control and mutant embryos; the neural tube  is unclosed at this stage in both control and mutant. Electron micrographs shown in Fig. 6 were obtained from these regions.  Bars: (B) 1 mm; (D) 0.25 mm; (F) 0.2 mm.
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Figure 5: Exencephaly in Lama5 −/− embryos. (A and B) Whole mount views of control and mutant embryos at E13.5. Exencephalics lack the skin and skull that normally enclose the brain and have a topologically “inside out” brain that does not develop properly. The skin and skull of the control was dissected away to allow direct comparison of mutant and normal brains. (C and D) Immunohistochemical localization of proliferating cells with anti-BrdU and alkaline phosphatase chemistry after labeling for 1 h in utero with BrdU. (C) In normal neural tissue (n), BrdU-labeled cells (arrow) are confined to the ventricular zone. v, ventricle. (D) In exencephalics, labeled cells (arrow) are found on the outer surface of the neural tissue. This surface would have been ventricular had the neural tube closed, but now it is in direct contact with amniotic fluid. Skin and skull (s) overlay the brain in the control but are missing from the mutant. Pia is indicated by dashed lines. (E and F) Toluidine blue–stained sections through the anterior of E8.7 control and mutant embryos; the neural tube is unclosed at this stage in both control and mutant. Electron micrographs shown in Fig. 6 were obtained from these regions. Bars: (B) 1 mm; (D) 0.25 mm; (F) 0.2 mm.
Mentions: In ∼60% of Lama5 −/− fetuses examined, the brain was enlarged and misshapen, and it was not covered by skin or skull (Fig. 5, A and B); the remaining mutants appeared to have grossly normal heads (data not shown). This partially penetrant defect is termed exencephaly, a condition in which the cranial vault fails to develop, and the tissues of the brain are exposed (Wallace and Knights, 1978). We do not know why this defect is partially penetrant, but we do note that partial penetrance has been observed in other mutant strains that exhibit exencephaly (Wallace and Knights, 1978; Macdonald et al., 1989; Vogelweid et al., 1993; Harris and Juriloff, 1997).

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