disabled-1 functions cell autonomously during radial migration and cortical layering of pyramidal neurons.
Genetic mosaics offer an excellent opportunity to analyze complex gene functions. Chimeras consisting of mutant and wild-type cells provide not only the avenue for lineage-specific gene rescue but can also distinguish cell-autonomous from non-cell-autonomous gene functions. Using an independent genetic marker for wild-type cells, we constructed Dab1(+/+) <--> Dab1(-/-) chimeras with the aim of discovering whether or not the function of Dab1 during neuronal migration and cortical layering is cell autonomous. Dab1(+/+) cells were capable of radial migration and columnar formation in a Dab1(-/-)environment. Most Dab1(+/+) cells segregated to the superficial part of the mutant cortex, forming a multilayered supercortex. Neuronal birth-dating studies indicate that supercortex neurons were correctly layered, although adjacent mutant cortex neurons were in reversed order. Immunocytochemistry using Emx1, a marker for pyramidal neurons, indicates that the vast majority of Dab1(+/+) neurons in the supercortex were Emx1 immunoreactive. Confirmation of the pyramidal phenotype was demonstrated by the absence of GABA immunoreactivity among Dab1(+/+) cells in the supercortex. Myelin staining using 2'3'-cyclic nucleotide 3'-phosphodiesterase showed the supercortex was supported by a secondary white matter from which thick fiber tracts appear connected to the underlying mutant white matter. The presence of Dab1(+/+) cells failed to rescue inversion of cortical layers and the abnormal infiltration of the marginal zone by Dab1(-/-) cells. Conversely, mutant cells did not impose a mutant phenotype on adjacent wild-type neurons. These results suggest that Dab1 functions cell autonomously with respect to radial migration and cortical layering of pyramidal neurons.
Hammond
V
V
Howard Florey Institute, The University of Melbourne, Parkville 3010, Victoria, Australia.
Howell
B
B
Godinho
L
L
Tan
S S
SS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D019070:Cell Lineage; D002465:Cell Movement; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005819:Genetic Markers; D018398:Homeodomain Proteins / Q000096:biosynthesis; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D019579:Neocortex / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology*; D009413:Nerve Fibers, Myelinated; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D014157:Transcription Factors; D018183:Transplantation Chimera; D000099260:Empty Spiracles Homeobox Proteins
D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C115785:DAB1 protein, human; C103773:Dab1 protein, mouse