Stem- and Progenitor Cell Proliferation in the Dentate Gyrus of the Reeler Mouse

Abstract

Adult hippocampal neurogenesis has been implicated in hippocampus-dependent learning and memory. Furthermore, the decline of neurogenesis accompanying aging could be involved in age-related cognitive deficits. It is believed that the neural stem cell niche comprises a specialized microenvironment regulating stem cell activation and maintenance. However, little is known about the significance of the extracellular matrix in controlling adult stem cells. Reelin is a large glycoprotein of the extracelluar matrix known to be of crucial importance for neuronal migration. Here, we examined the local interrelation between Reelin expressing interneurons and putative hippocampal stem cells and investigated the effects of Reelin deficiency on stem cell and progenitor cell proliferation. Reelin-positive cells are found in close vicinity to putative stem cell processes, which would allow for stem cell regulation by Reelin. We investigated the proliferation of stem cells in the Reelin-deficient reeler hippocampus by Ki67 labeling and found a strong reduction of mitotic cells. A detailed analysis of dividing Type 1, type 2 and type 3 cells indicated that once a stem cell is recruited for proliferation, the progression to the next progenitor stage as well as the number of mitotic cycles is not altered in reeler. Our data point to a role for Reelin in either regulating stem cell quiescence or maintenance.

Reelin-Related Disturbances in Depression: Implications for Translational Studies

“…We interpreted these observations to indicate that reelin downregulation may delay the maturation of newborn granule cells and impair proper integration of these neurons into mature circuits, thereby disrupting hippocampal circuitry and enhancing depression-like behavior. This conclusion is consistent with other findings that reeler mice (with null reelin expression) have fewer mitotic cells in the dentate SGZ than wildtype mice (Sibbe et al, 2015 ) and that inactivation of the reelin pathway impairs hippocampal adult neurogenesis (Teixeira et al, 2012 ). It also adds a new component to the prominent hypothesis that adult hippocampal neurogenesis plays a causal role in major depression (Jacobs et al, 2000 ).…”

Distinct synaptic and neurochemical changes to the granule cell-CA3 projection in Bassoon mutant mice

“…In the mature brain, Reelin is synthesized by a subpopulation of GABAergic interneurons (Drakew et al, 1998 ; Pesold et al, 1998 ). Reelin continues to play a role beyond development and has been implicated in the modulation of neurotransmission (Hellwig et al, 2011 ), NMDA receptor activity (Chen et al, 2005 ) and neurogenesis (Sibbe et al, 2015 ), and may underlie the granule cell dispersion (GCD) that characterizes the DG in temporal lobe epilepsy (TLE; Haas et al, 2002 ). To determine whether Reelin expression by inhibitory GABAergic interneurons was affected in the present model of neuronal hyperactivity, the DGs of Reelin-labeled hippocampi were examined.…”

Dab1 contributes differently to the morphogenesis of the hippocampal subdivisions

“…), and the stem cell niche is poorly established (Sibbe et al . ). The nature of Tbr2 positive cells requires further examination to determine the relevance of these possibilities.…”

“…Inwardly localized Tbr2 positive cells in the control DG might be produced from radially migrating neural stem cells toward the stem cell niche in the subgranular zone. In the Reelin-Dab1 signal deficient HF, only few stem cells can arrive at the subgranular zone (Brunne et al 2013), and the stem cell niche is poorly established (Sibbe et al 2015). The nature of Tbr2 positive cells requires further examination to determine the relevance of these possibilities.…”