TY - JOUR
T1 - Development of the proximal-anterior skeletal elements in the mouse hindlimb is regulated by a transcriptional and signaling network controlled by SALL4
AU - Chen, Katherine Q.
AU - Tahara, Naoyuki
AU - Anderson, Aaron
AU - Kawakami, Hiroko
AU - Kawakami, Sho
AU - Nishinakamura, Ryuichi
AU - Pandolfi, Pier Paolo
AU - Kawakami, Yasuhiko
N1 - Publisher Copyright:
Copyright © 2020 by the Genetics Society of America
PY - 2020/5
Y1 - 2020/5
N2 - The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf. We found that Sall4 regulates Plzf expression prior to hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in hindlimbs.
AB - The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf. We found that Sall4 regulates Plzf expression prior to hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in hindlimbs.
KW - Limb
KW - Plzf
KW - Proximal-anterior skeleton
KW - Sall4
KW - Sonic Hedgehog-Gli3
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UR - http://www.scopus.com/inward/citedby.url?scp=85084350539&partnerID=8YFLogxK
U2 - 10.1534/genetics.120.303069
DO - 10.1534/genetics.120.303069
M3 - Article
C2 - 32156750
AN - SCOPUS:85084350539
SN - 0016-6731
VL - 215
SP - 129
EP - 141
JO - Genetics
JF - Genetics
IS - 1
ER -