Cerebellar Purkinje cell loss in aging Hu-Bcl-2 transgenic mice.
The number of cerebellar Purkinje cells is increased by over 40% in young transgenic mice that overexpress a human Bcl-2 transgene (Hu-Bcl-2). To determine whether the Bcl-2-mediated rescue of Purkinje cells persists through life, the numbers of Purkinje cells were estimated in 6-, 12-, 18-, and 24-month-old Hu-Bcl-2 transgenic mice and age-matched controls. In addition, the expression of four markers for Purkinje cell differentiation, calbindin (CaBP), the 67-kDa isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid transaminase (GABA-T), and the NMDA-R1 receptor subtype (NMDA-NR1) was analyzed in 6-month-old Hu-Bcl-2 transgenics and controls to determine whether overexpression of Bcl-2 and rescue from naturally occurring cell death affects the normal differentiation of Purkinje cells. The estimates of Purkinje cell numbers showed that the number of Purkinje cells in the Hu-Bcl-2 transgenics declines after 6 months to approach wild-type values by 18 months. Although the exogenous human BCL-2 is still expressed in Purkinje cells at 24 months, the expression levels of human BCL-2 appear to decline significantly after 6 months, suggesting that survival of the supernumary Purkinje cells depends on the sustained overexpression of Bcl-2. All the Purkinje cells in the Hu-Bcl-2 transgenic mice appeared to express normal levels of the differentiation markers analyzed so there was no evidence for a class of Purkinje cells that do not differentiate normally when rescued from naturally occurring cell death.
Zanjani
Hadi
H
Lab. Développement et Vieillissement du Système Nerveux (DVSN), UMR NPA 7102 Centre National de la Recherche Scientifique and Université Pierre and Marie Curie, 75005 Paris, France.
Lemaigre-Dubreuil
Y
Y
Tillakaratne
Niranjala J K
NJ
Blokhin
Andrei
A
McMahon
Robert P
RP
Tobin
Allan J
AJ
Vogel
Michael W
MW
Mariani
Jean
J
D000612:4-Aminobutyrate Transaminase / Q000096:biosynthesis; D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D064026:Calbindins; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D011689:Purkinje Cells / Q000166:cytology* / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis
D064026:Calbindins; D007527:Isoenzymes; C409466:NR1 NMDA receptor; D019253:Proto-Oncogene Proteins c-bcl-2; D016194:Receptors, N-Methyl-D-Aspartate; D064030:S100 Calcium Binding Protein G; D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1