International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G2 Cerebellar Defects in HBNF-/-; MDK-/- Deficient Mice

Lorene Amet1, James H. Millonig2, Christine Gallagher2, Susan D. Croll3, John M. Levorse1, Bindu Prabhakaran1, Mary E. Hatten2, and Thomas F. Vogt1. 1Dept. of Molecular Biology, Princeton University, Princeton, NJ 08544; 2Rockefeller University, New York, NY 10021, 3 Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591

Neuronal progenitors proliferate during development in restricted areas of the CNS called ventricular zones. Proliferation of the cerebellar granule cells is an example of secondary neurogenesis. Granule cells are determined during embryogenesis in the rhombic lip but continue to proliferate postnatally in a specialized zone termed the external germinal layer (EGL). Heparin binding neurotrophic factor (Hbnf, also known as Ptn and HB-GAM) and midkine (Mdk) constitute the two members of a highly conserved vertebrate gene family encoding secreted proteins with mitogenic activities. Both Hbnf and Mdk are expressed in the rhombic lip and in granule cells of the neonatal EGL as well as throughout the developing nervous system in a pattern that reflects neuroectodermal proliferation. Gene-targeted disruptions of both Hbnf and Mdk have been created and the single mutants have been crossed to generate double homozygous mutants (Hbnf-/-;Mdk-/-).

Both the single and double homozygous mutants are viable and fertile. Analysis of the performance of the double mutants in a battery of behavioral assays reveals defects in balance and gait suggesting the possibility of a cerebellar defect. Histological examination of the brains of Hbnf-/-;Mdk-/- mice reveals a reduction in the overall size of the cerebellum and anatomical defects, including stunting and abnormal foliation.

Quantification of the mitotic index and cell death in the EGL of Hbnf-/-;Mdk-/- mice indicates a reduction in granule cell proliferation. A significant reduction in the poliferative capacity is also observed in granule cells from P6 mutant cerebellums following explant into culture. This proliferation defect is rescued by the addition of ecombinant Hbnf protein. The cerebellar defects in the midkine deficient mice demonstrate a required role for these molecules in the proliferation of cerebellar granule cells and indicates a potential general requirement for these genes in neuronal proliferation.

 


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