3Development‐Dependent Regulation of N‐Acetyl‐β‐d‐Hexosaminidase of Cerebellum and Cerebrum of Normal and Staggerer Mutant Mice

Abstract

Distinctive activities of various glycosidases were expressed in the cerebellum and cerebral cortex of mice during their development. In particular, N-acetyl-beta-D-hexosaminidase (EC 3.2.1.30) appeared to be developmentally regulated. A transient peak of enzyme activity at postnatal day 7 was characteristic for the cerebellum, whereas the activity in the cerebral cortex gradually increased through the 1st postnatal month and was maintained at a high level of activity throughout adulthood. The regulation of N-acetylhexosaminidase activity in the developing cerebellum of the staggerer mouse deviated clearly from enzyme activities in the wild-type, whereas the activity pattern in the staggerer cerebral cortex remained unaffected. In experiments mixing wild-type and staggerer cerebellum homogenates, the specific activity was additive. Thus, involvement of inhibitors or activating molecules can be excluded. This developmentally controlled regulation or disregulation in staggerer appears to be enzyme specific, sine beta-glucosidase, alpha-glucosidase, and beta-galactosidase did not exhibit such a pattern in either normal or staggerer mice. In the mutation weaver that, like staggerer, loses the majority of its cerebellar granule cells, N-acetyl-beta-hexosaminidase activity of the cerebellum was not elevated, indicating a specific defect in staggerer rather than a general effect on lysosomal enzymes due to cell death.

Cytological compartmentalization in the staggerer cerebellum, as revealed by calbindin immunohistochemistry for Purkinje cells

“…The developmental shift from multiple to single innervation of PCs by climbing fibers is also impaired (Crepel et al, 1980;Mariani and Changeux, 1980). In addition to these neurocytological deficits, several lines of evidence suggest that development of neurochemical and neurophysiological properties is retarded, such as the persistence of the immature type of cell surface carbohydrates (Hatten and Messer, 1978;Trenkner, 1979), late peaking of glycosidase activity (Wille et al, 1983), delayed developmental conversion of neural cell adhesion molecules (Edelman and Chuong, 1982), and persistent N-methyl-D-aspartate (NMDA) receptor-mediated responses (Dupont et al, 1984;Nakagawa et al, 1996a). Furthermore, expressions of particular genes, which attain striking levels in adult wild-type PCs, remain at low or undetectable levels in the staggerer PCs; these include the inositol 1,4,5-trisphosphate receptor type 1 (InsP 3 R1), metabotropic glutamate receptor type 1␣, calmodulin, calbindin, and L7/pcp-2 (Mallet et al, 1975;Furuichi et al, 1989;Messer et al, 1990;Ryo et al, 1993;Hamilton et al, 1996;Nakagawa et al, 1996b).…”

Analyses of temporal regulatory elements of the prosaposin gene in transgenic mice

“…Acid ceramidase mRNA was expressed in most adult tissues, including brain, and its expression in embryos was increased with the progression of gestation [37]. The β-N-acetyl--hexosaminidase appeared to be developmentally regulated, with a transient peak of enzyme activity at postnatal day 7 in cerebellum, and the activity in cerebral cortex gradually increased throughout adulthood [38]. Production of cathepsin D mRNA in rat brain continued at constant levels throughout development from E16 to postnatal day 15, and there was a moderate decrease at 64 days.…”

Regional Variation in Expression of Calbindin and Inositol 1,4,5‐trisphosphate Receptor Type 1 mRNAs in the Cerebellum of the Staggerer Mutant Mouse

“…There are several lines of evidence that suggest immaturity of the staggerer cerebellum. These include reduced cytoplasmic volume of the Purkinje cells (Yoon, 1976), multipolarity of their dendritic trees (Bradley and Berry, 1978), delayed disappearance of the external granular layer (Sidman, 1962), persistence of an immature type of cell surface carbohydrates (Hatten and Messer, 1978;Trenkner, 1979), late peaking of glycosidase activity (Wille et al, 1983) and delayed developmental conversion of neural cell adhesion molecules (Edelman and Chuong, 1982). In the wildtype cerebellum, calbindin-immunopositive and -immunonegative clusters appear transiently during neonatal stages, and exhibit an orthogonal arrangement (Wassef et al, 1985).…”