CXCR7 Receptor Signaling in the Nervous System

Hopkins, Brittany E

doi:https://doi.org/10.21985/n2-3ffx-c820

Work

CXCR7 Receptor Signaling in the Nervous System

Public

Download PDF

Chemokines, such as Stromal Derived Factor 1 (SDF-1 or CXCL12) and their G protein coupled receptors (GPCRs) are well known regulators of the development and functions of numerous tissues. CXCL12 has two receptors: CXCR4 and CXCR7 or atypical chemokine receptor 3 (ACKR3). CXCR7 has been described as an atypical “biased” receptor because it does not appear to signal through G proteins but does signal through β-arrestin. Because CXCR7 was deorphanized much later than CXCR4, we are still learning more about the unique roles of each receptor. This thesis explores CXCR7 mediated signaling with a focus on the nervous system. The work shown in Chapter 2 demonstrates that CXCR7 is not able to signal through any of the mammalian Gα protein isoforms. Two novel small molecule ligands for CXCR7 were characterized. The amino acid residue that is important for the ability of small molecule ligands to recruit β-arrestin to the receptor was identified. The development of more selective CXCR7 ligands should allow a better understanding of the unique roles of CXCR7 in the CXCL12/CXCR4/CXCR7 signaling axis as well as the structural determinants for CXCR7 activation. Chapters 3 and 4 focused on the role of CXCR7 in the Central Nervous System (CNS). There are established roles for CXCL12/CXCR4 in the CNS but much of this work was done before CXCR7 was deorphanized and, as such, less is known about the expression and roles of CXCR7 in the CNS. The expression pattern of CXCR7 was explored with a focus on examining where CXCR4 and CXCR7 are coexpressed, which can lead to heterodimer formation and differential signaling consequences. Examination of the expression pattern of the CXCR4 and CXCR7 receptors in vivo, in Chapter 3, revealed that both receptors are expressed in the developing cerebellum and also in a unique population of interneurons in the hilus of the dentate gyrus. As shown in Chapter 4, CXCR4 and CXCR7 are also coexpressed in neural stem cells in vitro. The coexpression of both receptors continues after the neural stem cells are differentiated. This work provides biological contexts, both in vivo and in vitro, in the developing and adult CNS where both CXCR4 and CXCR7 are expressed and in which receptor dimerization and/or CXCR7 regulated CXCR4 signaling may occur. This thesis furthers the understanding of the signaling capabilities of CXCR7, adds to the pool of selective pharmacological probes for CXCR7 and shows that CXCR4 and CXCR7 receptors are co-expressed in the CNS in vitro, in neural stem cells, and in vivo.

Creator