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PLoS One. 2015 Apr 15;10(4):e0124295. doi: 10.1371/journal.pone.0124295. eCollection 2015.

Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development.

Author information

1
Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, United States of America.
2
Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, United States of America; Department of Genetics, Yale School of Medicine, New Haven, Connecticut, United States of America; Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, United States of America.
3
Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, United States of America.
4
Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, United States of America; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, United States of America; Department of Genetics, Yale School of Medicine, New Haven, Connecticut, United States of America; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, United States of America.
5
Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, United States of America; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, United States of America; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, United States of America.

Abstract

Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development.

PMID:
25875176
PMCID:
PMC4398320
DOI:
10.1371/journal.pone.0124295
[Indexed for MEDLINE]
Free PMC Article

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