Dramatically Different Phenotypes in Computer mouse Models of Human Tay-Sachs and Sandhoff Diseases

Cross-sections of spine of wild type (a), Hexb −/− (B, D-G) and Hexa −/− (C) mice. (A-C) Light micrograph of ventrolateral areas from 3½ month older mice. (A) Wild sort showing lumbar level area. Note the normal higher density of myelin information in the peripheral bright matter.

Total cellular RNA was prepared coming from various mouse tissues which includes testis, epididymis, lung, liver, kidney, heart, spleen plus total brain and examined by Northern blot as described previously (17, 18). The hybridization probes from the Hexa and Hexb cDNA contained the whole coding sequences.

Hechtman and D. Mahuran, Meters. Fernandes and D. Trasler for advice and dicussion, K.

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(D, E)Hexb −/− are electron micrographs of a lumbar level section taken surrounding to the section within (B). (D) Shows abnormal fibers encountered throughout typically the section. (E) Shows profiles consistent with a fast loss in axonal integrity still ensheathed with largely undamaged myelin sheaths. Fibers filled with electron-dense axon users as well as apparently empty and collapsed myelin sheaths are present although no normal appearing axons with disrupted or absent myelin were observed. (F)Hexb −/− shows light micrograph of semithin section of dorsomedial gray matter.

Expression regarding Hexa and Hexb mRNAs

Brain extracts from a Hexb −/−mouse exposed negligible activity in the Hex B and Hex A new fractions. Minimal activity of a new third form of Hex, Hex S, an α dimer found in individual Sandhoff disease (23), was recovered by step elution with sodium citrate buffer, pH 3. 5 (Fig. 5Hexb −/−). There has been also trace activity eluting at pH 4. 4–4. 7 that may match Hex S precursor (20). A similar chromatofocusing completed with testis extracts from Hexb −/− mice got background activity, confirming that will the abundant one 7 kb β-subunit transcript do not encode a functional protein (data not shown). Coronal sections of human brain and spine from Hexa −/− (A-D) and Hexb −/− mice (E-H), 3–4½ months old, immunostained with mouse-human chimeric monoclonal antibody KM966 recognizing G M2.

  • H, hepatocytes; E, endothelial cell; S, sinusoid; Chemical, central vein of hepatic lobule; M, cell inside metaphase; T, cells found in telophase.
  • They were not able to right themselves when positioned on their back.
  • In contrast, dramatic structural differences between the Hexa −/− and Hexb −/− mice were observed in the spinal cord.
  • In the Hexb −/− mice, the activity with either substrate was lowered to below 1. five per cent.
  • Within the brain homogenate coming from a wild-type mouse (Fig. 5, wild type), the first MUG-active enzyme to elute from the column has been Hex B with a peak centered at ph level 6. 9 (range seven. 0–6. 5), followed by Hex A having a peak centered at pH 4. 8 (range 5. 1–4. 5).
  • Triggs-Raine for providing Hexb genomic clones and reading the manuscript, and M.

Generation and phenotype associated with Hexa −/− mice

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Franklin for consultation services on the neuropathology and for making plates from his forthcoming A Stereotaxic Atlas of the Mouse Brain (K. Franklin and G. Paxinos, eds, Academic Press) accessible prior to publication, Mirielle. Shevell for help with the particular phenotype, L. Old for helping make the ganglioside analysis possible, B.

T, testis; E, epididymis; Lu, chest; Li, liver; K, renal; H, heart; B, mind; S, spleen. ES tissues in 800 µl associated with cold PBS using a Bio-Rad GenePulser (240V, five-hundred µF).

(C) plus (F) are from outdoors type, (A), (D) plus (G) from Hexa −/− and (B), (E) and (H) from Hexb −/− mice. (A) and (B) Electron micrographs of cortical neurons showing large clusters of MCB. Some lysosomes have membrane whorls.

In the particular kidney, the cytoplasm associated with epithelial cells lining the particular proximal tubules showed considerable vacuolation (Fig. 7H). Renal corpuscles, distal convoluted tubules and collecting ducts came out normal. The nerve materials of both the heavy and ventral roots appeared normal in Hexa −/− and Hexb −/− rats.

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