Generation and characterization of mice harboring a conditional CXCL12 allele.
The chemokine CXCL12 has important functions in immune and central nervous systems. Moreover, a global disruption of CXCL12 in mice results in perinatal lethality. To circumvent this impediment and provide a tool for analyzing CXCL12 functions in specific organ systems, we have generated a mouse line harboring a loxP-site flanked exon 2 of CXCL12. A germ line deleter, β-actin::cre was used to remove a CXCL12 exon 2 and subsequently systemic CXCL12 exon 2 deficient embryos were generated. These mutant embryos showed a marked depletion of CXCL12 transcript. As expected from the global mutant phenotype, our mutants were also characterized by highly irregular cerebellar cytoarchitecture of the external granule layer as well as altered radial migration of midbrain dopaminergic neurons. Importantly, migration of the pontine grey nucleus (PGN) was derailed and remarkably resembled the global mutant phenotype of the CXCL12 receptor - CXCR4 in this system. Despite the fact that CXCL12 signaling can be mediated through receptors other than CXCR4, our results indicate a monogamous relationship between the CXCL12 ligand and CXCR4 receptor in controlling PGN migration. Our findings further expand on the understanding of CXCL12 function in PGN development. Moreover, phenotypic similarities between our mutants and mice harboring a global CXCL12 disruption support the validity of our line. Importantly, these results strongly suggest that our conditional CXCL12 line can be used as a powerful tool to manipulate CXCL12 signaling and function in vivo.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
Ryan E
RE
Hillmer
Joanne P
JP
Boisvert
Monica J
MJ
Cucciare
Michael B
MB
Dwinell
Milan
M
Joksimovic
D000483:Alleles; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D011149:Pons / Q000002:abnormalities / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
D054377:Chemokine CXCL12