Migration of transplanted neural progenitor cells in a ferret model of cortical dysplasia.
Although altered gene expression clearly causes failure of the neocortex to form properly, many causes of neocortical dysplasia arise from environmental or unknown factors. Our lab studies a model of cortical dysplasia induced by injection of methylazoxymethanol (MAM) into pregnant ferrets on embryonic day 33 (E33), which shares many features of neocortical dysplasia in humans. E33 MAM treatment results in characteristic deficits that include dramatic reduction of layer 4 in somatosensory cortex, widespread termination of thalamic afferents, and altered distribution of GABAergic elements. We determined the ability of immature cells to migrate into MAM-treated cortex using ferret neural progenitor cells obtained at E27 and E33 and mouse neural progenitor cells obtained at E14. When these cells were transplanted into organotypic cultures obtained from normal and E33 MAM-treated ferret cortex prepared on postnatal day 0 (P0), all progenitor cells migrated similarly in both hosts, preferentially residing in the upper cortical plate. The site of transplantation was significant, however, so that injections into the ventricular zone were more likely to reach the cortical plate than transplants into the intermediate zone. When similar cells were transplanted into ferret kits, approximately P7-P9, and allowed to survive for 2-4 weeks, the donor cells migrated differently and also reached distinct destinations in normal and MAM-treated hosts. MAM-treated cortex was more permissive to invasion by donor cells as they migrated to widespread aspects of the cortex, whereas transplants in normal host cortex were more restricted. E27 neural progenitor cells populated more cortical layers than later born E33 neural progenitor cells, suggesting that the fate of transplanted cells is governed by a combination of extrinsic and intrinsic factors.
Program in Neuroscience, USUHS, Bethesda, MD 20814, USA.
Alisa W
AW
Schaefer
Sharon L
SL
Juliano
D000596:Amino Acids / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005289:Ferrets; D054220:Malformations of Cortical Development / Q000139:chemically induced / Q000628:therapy*; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000502:physiology
D000596:Amino Acids; D009419:Nerve Tissue Proteins; C098463:dolaisoleucine; D008746:Methylazoxymethanol Acetate; C030667:methylazoxymethanol