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Sci Rep. 2017 Jul 28;7(1):6771. doi: 10.1038/s41598-017-06964-9.

Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development.

Author information

1
Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, Tokyo, 160-8582, Japan. kazukikodo.a3@keio.jp.
2
Department of Physiology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
3
Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
4
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305-5111, USA.
5
Department of Neurology, National Hospital Organization, Tottori Medical Center, Tottori, Tottori, 689-0203, Japan.
6
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
7
Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, Tokyo, 160-8582, Japan. hyamag@keio.jp.

Abstract

The cardiac neural crest cells (cNCCs) and the second heart field (SHF) play key roles in development of the cardiac outflow tract (OFT) for establishment of completely separated pulmonary and systemic circulations in vertebrates. A neurovascular guiding factor, Semaphorin 3c (Sema3c), is required for the development of the OFT, however, its regulation of the interaction between cNCCs and SHF remains to be determined. Here, we show that a Sema3c is a candidate that mediates interaction between cNCCs and the SHF during development of the OFT. Foxc1/c2 directly activates the transcription of Sema3c in the OFT, whereas, a hypomorph of Tbx1, a key SHF transcription factor, resulted in the ectopic expression of Sema3c in the pharyngeal arch region. Fgf8, a downstream secreted factor of Tbx1, inhibited the expression of Sema3c in cNCCs via activation of ERK1/2 signaling. Blocking of FGF8 caused ectopic expression of SEMA3C and a migration defect of cNCCs, resulting in abnormal chick pharyngeal arch development. These results suggest that proper spatio-temporal expression of Sema3c, regulated positively by Foxc1/c2 and negatively by the Tbx1-Fgf8 cascade, respectively, is essential for the interaction between cNCCs and the SHF that correctly navigates cNCCs towards the OFT, composed of SHF-derived cells.

PMID:
28754980
PMCID:
PMC5533775
DOI:
10.1038/s41598-017-06964-9
[Indexed for MEDLINE]
Free PMC Article

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