Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons

Abstract

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.

Dopaminergic neurons modulate GABA neuron migration in the embryonic midbrain

“…Neuronal migration silhouette in the mesencephalon BrdU birthdating studies have been widely used to study neuronal migration in the developing neocortex (López-Bendito et al, 2008;Mathis et al, 2010;Ori-McKenney and Vallee, 2011;Soriano and Del Rio, 1991;Supèr et al, 2000;Wines-Samuelson et al, 2005). Because BrdU is integrated into the DNA of S-phase progenitor cells, it serves as a stable marker for cells born around .…”

Selective expression of presenilin 1 in neural progenitor cells rescues the cerebral hemorrhages and cortical lamination defects in presenilin 1-null mutant mice

“…S3 in the supplementary material), and reelin immunostaining (see Fig. S4 in the supplementary material) showed that Cajal-Retzius cells were as easily identified in the marginal zone of rescued animals as in wild-type embryos, showing no evidence for the loss of these cells that occurs in latter stage Psen1 -/-embryos (Hartmann et al, 1999;Kilb et al, 2004;Wines-Samuelson et al, 2005). Indeed, except for pure Psen1 -/-embryos, there were no differences between wild-type embryos and any of the genotypes that were generated in these crosses (i.e.…”

Conditional Inactivation of Presenilin 1 Prevents Amyloid Accumulation and Temporarily Rescues Contextual and Spatial Working Memory Impairments in Amyloid Precursor Protein Transgenic Mice

“…A major problem with this strategy is that presenilin 1 (PS1) plays essential roles in vivo (Wong et al, 1997;Xia et al, 2001;Pan et al, 2004), including neuronal differentiation and migration during embryonic development (Shen et al, 1997;Handler et al, 2000;Wines-Samuelson et al, 2005). However, PS1 conditional knock-out (PS1 cKO) mice, in which PS1 inactivation is restricted to the postnatal forebrain, show reduced A␤ generation and only subtle spatial memory impairment (Yu et al, 2001).…”