Deletion of brain dystroglican recapitulates aspects of congenital muscular dystrophy S.A. Moore, F. Salto, J.Chen, D.E. Michele, M.D. Henry, A. Messing, R.D, Cohn, S. E. Ross-Barta, S. Westra, R.A. Williamson, T. Hoshi, K. P. Campbell
Nature V. 418. No 6896. P.422-425. 2002
Nature V. 418. No 6896. P.422-425. 2002
Дистрогликан является высоко гликозилированным компонентом мышечного дистрофин-гликопротеинового комплекса, который экспрессируется и в головном мозге. избирательная делеция дистрогликана в головном мозге достаточна для возникновения нарушений головного мозга, обычно сопровождающих CMDs, включая нарушение образования кортикальных слоев, слияние полушарий головного мозга и мозжечкового листка (folia)и аберрантную миграцию гранулярных клеток. Такой головной мозг теряет связывание с высоким сродством белка ламинина ВКМ и обнаруживает непрерывность пиальной поверхности базальной ламины (glia limitans), которая, по-видимому, и обусловливает ошибки в миграции нейронов. Установлено, что дистрогликан может играть и постсинаптическую роль в процессах обучения и памяти.
(Рис.1.suppl) | (a) Design of floxed dystroglycan mice.
(b) Dystroglycan rtPCR from total brain RNA. Gene specific sense primer (5'-GCTCATTTCGAGTGAGCATTCC- 3') and antisense primer (5'-CTAGTTTCCAGGACAGGAGA- 3') were designed to anneal to the sequences in exon 1 and exon 2, respectively.
(c) Tissue -selective recombination of floxed dystroglycan gene . Gene specific sense primer (5'-CGAACACTGAGTTCATCC-3') and antisense primer (5'-CAACTGCTGCATCTCTAC-3') were designed to anneal to the intronic sequences flanking exon 2, which allow amplification of a 585 bp fragment only when exon 2 and the neo cassette are excised by Cre recombinase.
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(Рис.1.suppl) | (a) Design of floxed dystroglycan mice.
(b) Dystroglycan rtPCR from total brain RNA. Gene specific sense primer (5'-GCTCATTTCGAGTGAGCATTCC- 3') and antisense primer (5'-CTAGTTTCCAGGACAGGAGA- 3') were designed to anneal to the sequences in exon 1 and exon 2, respectively.
(c) Tissue -selective recombination of floxed dystroglycan gene . Gene specific sense primer (5'-CGAACACTGAGTTCATCC-3') and antisense primer (5'-CAACTGCTGCATCTCTAC-3') were designed to anneal to the intronic sequences flanking exon 2, which allow amplification of a 585 bp fragment only when exon 2 and the neo cassette are excised by Cre recombinase.
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(Рис.2. suppl) | Macrocephaly. Photographs are from littermate control and GFAP -Cre/DG-null mice(dorsal surfaces and coronal sections). Graphs are brain weights from littermate pairs. Brain weights are increased by 17.7% in DG-null females (p=0.00002; 13 littermate pairs) and by 18.2% in DG-null males (p=0.00004; 9 littermate pairs). Brain/body weight ratios are also increased in DG-null mice (20.5% increase in females, p=0.009; 30.3% increase in males, p=0.008).
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(Рис.3. suppl) | ementary) Cerebral neuronal migration abnormalities. H&E stained sections from littermate control (a, c, and e) and GFAP-Cre/DG-null (b, d, and f) mice show midline fusion (vertical arrows), disarray of neuronal migration, and normal location of anterior cerebral artery, corpus callosum (cc), and lateral ventricle (v).
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(Рис.4. suppl) | Cerebellar and brain stem neuronal migration abnormalities. H&E stained sections from littermate control (a, b, c, and g) and GFAP-Cre/DG-null (d, e, f, h, i, and j) cerebella and DG-null brain stem (k and l). Arrows in (e) mark fusion of adjacent folia, while arrows in (f) show subependymal, heterotopic cerebellar cortex. Regions of abnormal granule cell migration are labeled “egc” in (e) and marked by dashed white ova ls in (h) and (i) or arrows in (j). Panels a-f, k and j are from adult mice. Panels g-j are from postnatal day 12 mice.
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(Рис.5. suppl) | Glial-neuronal meningeal heterotopia. Electron micrographs from littermate control and GFAP-Cre/DG-null mice. The normally open suba rachnoid space (a) is filled with heterotopic astrocytic and neuronal processes in DG-null mice (b). Arrows mark the location of the glia limitans in each micrograph. Brain parenchyma is at the bottom of each micrograph.