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Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background.
Proc Natl Acad Sci U S A 1998; 95(24):14517-22PN

Abstract

The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an approximately 50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKCepsilon expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKCepsilon expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes.

Authors+Show Affiliations

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. rkm@mail.med.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9826732

Citation

McNamara, R K., et al. "Effect of Reduced Myristoylated Alanine-rich C Kinase Substrate Expression On Hippocampal Mossy Fiber Development and Spatial Learning in Mutant Mice: Transgenic Rescue and Interactions With Gene Background." Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 24, 1998, pp. 14517-22.
McNamara RK, Stumpo DJ, Morel LM, et al. Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background. Proc Natl Acad Sci USA. 1998;95(24):14517-22.
McNamara, R. K., Stumpo, D. J., Morel, L. M., Lewis, M. H., Wakeland, E. K., Blackshear, P. J., & Lenox, R. H. (1998). Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background. Proceedings of the National Academy of Sciences of the United States of America, 95(24), pp. 14517-22.
McNamara RK, et al. Effect of Reduced Myristoylated Alanine-rich C Kinase Substrate Expression On Hippocampal Mossy Fiber Development and Spatial Learning in Mutant Mice: Transgenic Rescue and Interactions With Gene Background. Proc Natl Acad Sci USA. 1998 Nov 24;95(24):14517-22. PubMed PMID: 9826732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background. AU - McNamara,R K, AU - Stumpo,D J, AU - Morel,L M, AU - Lewis,M H, AU - Wakeland,E K, AU - Blackshear,P J, AU - Lenox,R H, PY - 1998/11/25/pubmed PY - 1998/11/25/medline PY - 1998/11/25/entrez SP - 14517 EP - 22 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 95 IS - 24 N2 - The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an approximately 50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKCepsilon expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKCepsilon expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/9826732/Effect_of_reduced_myristoylated_alanine_rich_C_kinase_substrate_expression_on_hippocampal_mossy_fiber_development_and_spatial_learning_in_mutant_mice:_transgenic_rescue_and_interactions_with_gene_background_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9826732 DB - PRIME DP - Unbound Medicine ER -