Abstract
Calretinin (CR) and calbindin D-28k (CB) are cytosolic EF-hand Ca2+-binding proteins and function as Ca2+ buffers affecting the spatiotemporal aspects of Ca2+ transients and possibly also as Ca2+ sensors modulating signaling cascades. In the adult hippocampal circuitry, CR and CB are expressed in specific principal neurons and subsets of interneurons. In addition, CR is transiently expressed within the neurogenic dentate gyrus (DG) niche. CR and CB expression during adult neurogenesis mark critical transition stages, onset of differentiation for CR, and the switch to adult-like connectivity for CB. Absence of either protein during these stages in null-mutant mice may have functional consequences and contribute to some aspects of the identified phenotypes. We report the impact of CR- and CB-deficiency on the proliferation and differentiation of progenitor cells within the subgranular zone (SGZ) neurogenic niche of the DG. Effects were evaluated (1) two and four weeks postnatally, during the transition period of the proliferative matrix to the adult state, and (2) in adult animals (3 months) to trace possible permanent changes in adult neurogenesis. The absence of CB from differentiated DG granule cells has no retrograde effect on the proliferative activity of progenitor cells, nor affects survival or migration/differentiation of newborn neurons in the adult DG including the SGZ. On the contrary, lack of CR from immature early postmitotic granule cells causes an early loss in proliferative capacity of the SGZ that is maintained into adult age, when it has a further impact on the migration/survival of newborn granule cells. The transient CR expression at the onset of adult neurogenesis differentiation may thus have two functions: (1) to serve as a self-maintenance signal for the pool of cells at the same stage of neurogenesis contributing to their survival/differentiation, and (2) it may contribute to retrograde signaling required for maintenance of the progenitor pool.
Highlights
Adult neurogenesis is the process of generating functional neurons from adult neuronal precursors
The thickness of the granule cell layer (GCL) is normal, as well as the morphology of the mature granule cells (CB-ir in wild type (WT) and CR−/− mice) and the not-yet fully differentiated ones bordering to the subgranular zone (SGZ) (CB-negative in WT and CR−/− mice)
At 2 weeks of age, morphogenesis of the infrapyramidal blade of the dentate gyrus (DG) is well completed, the proliferative matrix has rearranged along the SGZ and implementation of the inner third of the adult DG is ongoing, a gradual process that lasts till the end of the first postnatal month (Altman and Bayer, 1990a,b; Li and Pleasure, 2005)
Summary
Adult neurogenesis is the process of generating functional neurons from adult neuronal precursors. Intermediate transitional stages are consistently present, characterized by proliferating cells typically expressing both nestin and DCX (Brown et al, 2003; Ming and Song, 2011; von Bohlen Und Halbach, 2011). Progenitors realign their processes in a vertical direction and leave the SGZ to migrate a short distance into the lower granular layer at the border of the SGZ. The critical phase of cell cycle exit correlates with the onset of transient expression of the Ca2+-binding protein calretinin (CR) (Ming and Song, 2011; von Bohlen Und Halbach, 2011)
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