Impaired Generation of Transit-Amplifying Progenitors in the Adult Subventricular Zone of Cyclin D2 Knockout Mice.

Rafał Płatek,Marta B Wiśniewska,Piotr Rogujski,Artur Czupryn,Jarosław Mazuryk,Leszek Kaczmarek

doi:10.3390/cells11010135

Abstract

In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ—the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases.

Highlights

Most adult mammals are capable of producing new neurons in the brain [1,2]
We studied the proliferative activity of cells along the anterior–posterior and dorso–ventral axes of the subventricular zone (SVZ), in a series of 30-μm-thick coronal brain sections from cyclin D2 knockout (cD2-KO) and wild type mice (WT) mice
The number of dividing cells was calculated for all three walls of the SVZ: the dorsal, medial, and lateral walls (D, M, and L, respectively; see Figure 1A), while, in the caudal compartment, it was calculated for only two walls: the lateral and dorsal walls (Figure 1B)

Summary

Introduction

Most adult mammals are capable of producing new neurons in the brain [1,2] This so-called “adult neurogenesis” (proliferation and differentiation from neural precursors) occurs in specific neurogenic brain regions—the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), and the subventricular zone (SVZ), referred to as the subependymal zone, along the lateral ventricles [2,3,4,5]. CD2-KO mice showed quite severe olfactory dysfunctions, as they were unable to find hidden food under the cage bedding [17] This suggests that the continuous addition of SVZ-derived newly generated neurons to the OB network is important for proper olfaction and smell discrimination, and that cyclin D2 seems to be an important regulator of this process

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