CXCL12‐mediated feedback from granule neurons regulates generation and positioning of new neurons in the dentate gyrus

Abstract

Adult hippocampal neurogenesis is implicated in learning and memory processing. It is tightly controlled at several levels including progenitor proliferation as well as migration, differentiation and integration of new neurons. Hippocampal progenitors and immature neurons reside in the subgranular zone (SGZ) and are equipped with the CXCL12-receptor CXCR4 which contributes to defining the SGZ as neurogenic niche. The atypical CXCL12-receptor CXCR7 functions primarily by sequestering extracellular CXCL12 but whether CXCR7 is involved in adult neurogenesis has not been assessed. We report that granule neurons (GN) upregulate CXCL12 and CXCR7 during dentate gyrus maturation in the second postnatal week. To test whether GN-derived CXCL12 regulates neurogenesis and if neuronal CXCR7 receptors influence this process, we conditionally deleted Cxcl12 and Cxcr7 from the granule cell layer. Cxcl12 deletion resulted in lower numbers, increased dispersion and abnormal dendritic growth of immature GN and reduced neurogenesis. Cxcr7 ablation caused an increase in progenitor proliferation and progenitor numbers and reduced dispersion of immature GN. Thus, we provide a new mechanism where CXCL12-signals from GN prevent dispersion and support maturation of newborn GN. CXCR7 receptors of GN modulate the CXCL12-mediated feedback from GN to the neurogenic niche.

Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain

“…CXCR7, a non-classical G-protein-coupled receptor, is involved in CXCL12-mediated cell cycle regulation and cell proliferation [23,24]. AMD3100, a CXCR7 agonist, has been reported to induce the transformation of microglia into the anti-inflammatory M2 subtype and astrocytes into the neuroprotective A2 subtype [25,26].…”

The systemic exercise-released chemokine lymphotactin/XCL1 modulates in vitro adult hippocampal precursor cell proliferation and neuronal differentiation

“…Although XCL1 has not been previously linked to adult neurogenesis, other work has emphasized the importance of chemokine signalling in the regulation of NPCs in the hippocampal stem cell niche 12,15,16 . XCL1 represents an unusual type of chemokine, in that it lacks two of the four cysteine residues that are typical of all other chemokine families 27 , making it an interesting candidate to exert functions other than chemoattraction through the XCR1 receptor 24 .…”

“…Recent work in the ageing field shows that chemokines can influence adult hippocampal neurogenesis 12 , and it is known that NPCs express several chemokine receptors 13 . One example that underpins the importance of chemokine signalling in the neurogenic niche is stromal cell-derived factor 1-mediated signalling, which promotes the proliferation 14 and maturation 15 of NPCs, as well as the maintenance of the neural stem cell pool in the DG 16 . Moreover, the platelet-derived chemokine platelet factor 4, which is released into the blood following exercise, was recently shown to stimulate neurogenesis, particularly neuronal differentiation 2 .…”

Behavioral Feeding Circuit: Dietary Fat-Induced Effects of Inflammatory Mediators in the Hypothalamus

“…Since then, several chemokines have been linked to metabolism and brain neurochemicals, and given the nature of chemokines, may also be involved in the neurogenesis effects of a HFD on hypothalamic peptide neurons. The chemokine CXCL12 has been shown to be involved in neurogenesis events by regulating neuronal migration and proliferation in several brain regions (150)(151)(152)(153) and controlling neuropositioning of newly-born neurons (154). Knockdown of CXCL12 causes impaired proliferation, migration, and differentiation of neurons (145,155) suggesting modifications to this system can effect peptide neuron formation during pregnancy.…”