TY - JOUR
T1 - Disruption of Smad4 in neural crest cells leads to mid-gestation death with pharyngeal arch, craniofacial and cardiac defects
AU - Nie, Xuguang
AU - Deng, Chu xia
AU - Wang, Qin
AU - Jiao, Kai
N1 - Funding Information:
We thank Drs. B. Yoder (UAB), C. Haycraft (UAB), B. Zhou (Vanderbilt), S. Baldwin (Vanderbilt), C. Chiang (Vanderbilt) and R. Maxson (U. Southern CA) for providing various in situ probes. We thank Dr. V. Kaartinen (U. Southern CA) for valuable suggestions on India ink injection. We thank members of the Jiao laboratory for assistance on the project. We thank Drs. C. Haycraft and C. Chang (UAB) for critically reading and commenting on the manuscript. This project is supported by the Scientist Development Grant from AHA (National Center), a NIH grant (1R21HL085510-01) and a HSF-GEF Scholar Award to K.J.
PY - 2008/4/15
Y1 - 2008/4/15
N2 - TGFβ/BMP signaling pathways are essential for normal development of neural crest cells (NCCs). Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of TGFβ/BMP signaling. In this work, we sought to investigate the roles of Smad4 for development of NCCs. To overcome the early embryonic lethality of Smad4 null mice, we specifically disrupted Smad4 in NCCs using a Cre/loxP system. The mutant mice died at mid-gestation with defects in facial primordia, pharyngeal arches, outflow tract and cardiac ventricles. Further examination revealed that mutant embryos displayed severe molecular defects starting from E9.5. Expression of multiple genes, including Msx1, 2, Ap-2α, Pax3, and Sox9, which play critical roles for NCC development, was downregulated by NCC disruption of Smad4. Moreover, increased cell death was observed in pharyngeal arches from E10.5. However, the cell proliferation rate in these areas was not substantially altered. Taken together, these findings provide compelling genetic evidence that Smad4-mediated activities of TGFβ/BMP signals are essential for appropriate NCC development.
AB - TGFβ/BMP signaling pathways are essential for normal development of neural crest cells (NCCs). Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of TGFβ/BMP signaling. In this work, we sought to investigate the roles of Smad4 for development of NCCs. To overcome the early embryonic lethality of Smad4 null mice, we specifically disrupted Smad4 in NCCs using a Cre/loxP system. The mutant mice died at mid-gestation with defects in facial primordia, pharyngeal arches, outflow tract and cardiac ventricles. Further examination revealed that mutant embryos displayed severe molecular defects starting from E9.5. Expression of multiple genes, including Msx1, 2, Ap-2α, Pax3, and Sox9, which play critical roles for NCC development, was downregulated by NCC disruption of Smad4. Moreover, increased cell death was observed in pharyngeal arches from E10.5. However, the cell proliferation rate in these areas was not substantially altered. Taken together, these findings provide compelling genetic evidence that Smad4-mediated activities of TGFβ/BMP signals are essential for appropriate NCC development.
KW - Facial primordia
KW - Neural crest cells
KW - Outflow tract
KW - Pharyngeal arch
KW - Pharyngeal arch artery
KW - Smad4
UR - http://www.scopus.com/inward/record.url?scp=41149143019&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41149143019&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2008.02.006
DO - 10.1016/j.ydbio.2008.02.006
M3 - Article
C2 - 18334251
AN - SCOPUS:41149143019
SN - 0012-1606
VL - 316
SP - 417
EP - 430
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -