Aberrant dentate gyrus cytoarchitecture and fiber lamination in Lis1 mutant mice.
Mutant mice with a heterozygous deletion of LIS1, show varying degrees of hippocampal abnormality and enhanced excitability. To examine how LIS1 affects cytoarchitecture and fiber lamination in dentate gyrus (DG), we performed a series of immunohistochemistry studies. By using different neuronal- and glial-specific antibodies, we found that the majority of hippocampal cell populations were affected by heterozygous mutation of LIS1; some reelin-positive Cajal-Retzius cells were left undisturbed. Granule cell dispersion was significant in hippocampal sections from Lis1-deficient mice. However, the fiber termination of commissural/associational fibers and mossy fibers appeared relatively compact despite obvious granule cell dispersion and CA1-CA3 pyramidal cell disorganization. vGlut1-immunoreactive axon terminals were found aberrantly traversing the dispersed granule cell layer. Consistent with previous observations, we also found that immature granule cells in Lis1 mutants, here stained with antibodies to doublecortin (DCX) and Mash-1, are aberrantly located and bear an abnormal cellular morphology. Our findings suggest that LIS1 mutants exhibit abnormal cell positioning and aberrant hippocampal neurogenesis, but maintain relatively normal fiber termination patterns. The functional consequences of hippocampal granule cell dispersion could offer critical insight to the epileptic and cognitive disorder associated with LIS1 haploinsufficiency.
Wang
Yanling
Y
Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.
Baraban
Scott C
SC
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D018891:Dentate Gyrus / Q000002:abnormalities* / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D054082:Lissencephaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D016326:Extracellular Matrix Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D000091042:Reelin Protein; D012697:Serine Endopeptidases; C499317:Ascl1 protein, mouse; C000714328:DCX protein, human; C000714847:Dcx protein, mouse; C513190:Pafah1b1 protein, mouse; C000717127:RELN protein, human; C000717128:Reln protein, mouse