Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the “twitcher” mouse model of globoid cell leukodystrophy

Abstract

The twitcher mouse is well known as a naturally occurring authentic mouse model of human globoid cell leukodystrophy (GLD; Krabbe disease) due to genetic deficiency of lysosomal galactosylceramidase. The twitcher mice used most commonly are on the C57BL/6J background. We generated twitcher mice that were on the mixed background of C57BL/6J and 129SvEv, the standard strain for production of targeted mutations. Twitcher mice on the mixed background were smaller and had a shorter lifespan than were those on the C57BL/6J background. Many twitcher mice on the mixed background developed generalized seizures around 30 days that were never seen in twitcher mice on the C57BL/6J background. Neuropathologically, although the degree of the typical demyelination with infiltration of macrophages was similar in the central and peripheral nervous systems, in both strains, marked neuronal cell death was observed only in twitcher mice on the mixed background. In the hippocampus, the neuronal cell death occurred prominently in the CA3 region in contrast to the relatively well-preserved CA1 and CA2 areas. This neuropathology has never been seen in twitcher mice on the C57BL/6J background. Biochemically, the brain of twitcher mice on the mixed background showed much greater accumulation of lactosylceramide. Genetic background must be carefully taken into consideration when phenotype of mutant mice is evaluated, particularly because most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. These findings also suggest an intriguing possibility of important function of some sphingolipids in the hippocampal neuronal organization and maintenance.

Gastric Pit Cell Hyperplasia and Glandular Atrophy in Carbonic Anhydrase IX Knockout Mice: Studies on Two Strains C57/BL6 and BALB/C

“…It is generally recognized that most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. It is also common in many laboratories that the phenotype of such mutants seems to shift in time as the mice are back-crossed to a more homogenous background (Tominaga et al, 2004). Therefore, the present study was designed to back-cross first the mice into the pure C57/BL6 or BALB/c genetic backgrounds that provided genetically homogenous mouse strains which are also commonly used in research laboratories.…”

The Role of the Endothelium In Globoid-Cell Leukodystrophy: Unexpected Revelations

“…It must be pointed out that the altered metabolism of sphingolipids other than psychosine may also have powerful systemic effects in GLD. For instance, increased concentrations of lactosylceramide [22], a lipid raft component implicated in cell-cell and cell-matrix interactions and in signaling events linked to cell differentiation, apoptosis, development and oncogenesis [23], may contribute to tissue injury. In addition, GALC silencing may decrease intra cellular ceramide and sphingosine, thus affecting cell survival and function [18].…”

Regional expression of prosaposin in the wild-type and saposin D-deficient mouse brain detected by an anti-mouse prosaposin-specific antibody

“…23) The mice were anesthetized with ether and perfused through the left ventricle of the heart briefly with physiological saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer (PB) (pH 7.4) and immersed in the same fixative at 4 °C overnight. Then the brain was dissected and processed for sectioning.…”