Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons.
Presenilin-1 (PS1), the major causative gene of familial Alzheimer disease, regulates neuronal differentiation and Notch signaling during early neural development. To investigate the role of PS1 in neuronal migration and cortical lamination of the postnatal brain, we circumvented the perinatal lethality of PS1-null mice by generating a conditional knockout (cKO) mouse in which PS1 inactivation is restricted to neural progenitor cells (NPCs) and NPC-derived neurons and glia. BrdU birthdating analysis revealed that many late-born neurons fail to migrate beyond the early-born neurons to arrive at their appropriate positions in the superficial layer, while the migration of the early-born neurons is largely normal. The migration defect of late-born neurons coincides with the progressive reduction of radial glia in PS1 cKO mice. In contrast to the premature loss of Cajal-Retzius (CR) neurons in PS1-null mice, generation and survival of CR neurons are unaffected in PS1 cKO mice. Furthermore, the number of proliferating meningeal cells, which have been shown to be important for the survival of CR neurons, is increased in PS1-null mice but not in PS1 cKO mice. These findings show a cell-autonomous role for PS1 in cortical lamination and radial glial development, and a non-cell-autonomous role for PS1 in CR neuron survival.
Wines-Samuelson
Mary
M
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Handler
Melissa
M
Shen
Jie
J
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D044127:Epigenesis, Genetic; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000378:metabolism*; D008578:Meninges / Q000254:growth & development; D051379:Mice / Q000254:growth & development*; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D053764:Presenilin-1; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology*; D001616:beta-Galactosidase
D008565:Membrane Proteins; D053764:Presenilin-1; D051880:Receptors, Notch; D001616:beta-Galactosidase; D001973:Bromodeoxyuridine