Institute for Frontier Life and Medical Sciences, Kyoto University

A mechanism inhibiting a cartilage formation in the heart

Hiroyuki N. Arai1、Fuminori Sato1、Takuya Yamamoto 2、Knut Woltjen 2、Hiroshi Kiyonari 3、Yuki Yoshimoto 4、Chisa Shukunami 4、Haruhiko Akiyama 5、Ralf Kist 6、Atsuko Sehara-Fujisawa 1

(1 Institute for Frontier Life and Medical Sciences, Kyoto University, 2 Center for iPS Cell Research and Application (CiRA), Kyoto University, 3 RIKEN Center for Biosystems Dynamics Research, 4 Hiroshima University, 5 Gifu University, 6 Newcastle University)

 

”Metalloprotease-dependent attenuation of BMP signaling restricts cardiac neural crest cell fate”

Cell Reports(2019) DOI:10.1016/j.celrep.2019.09.019

Abstract

The vertebrate body has a unique population of cells called “neural crest cells”. These cells emerge as multipotent stem/progenitor cells, which can differentiate into various types of cells such as neurons, melanocytes, and chondrocytes. During development, neural crest cells originate from the dorsal side of the body, then migrate throughout the body. Therefore, proper differentiation of neural crest cells at an appropriate location is important for body formation. A subpopulation of neural crest cells called cardiac neural crest cells (CNCCs) migrate to the heart and contribute to the formation of blood vessels, valves, and ventricular septum in the heart.

This study presents that CNCCs usually form the tendon/ligament-like tissue between Aorta and pulmonary artery, whereas, in Adam19-deficient mice, these cells form ectopic cartilages in their hearts.

Adam19 is a membrane-anchored metalloprotease that cleaves (cuts off) proteins such as membrane growth factors in cell membranes, but the physiological substrate of Adam19 has been unknown.

Comprehensive gene expression profiling using microarray revealed that Adam19-deficient CNCCs showed the upregulation of Sox9 gene, which plays an important role in chondrogenic differentiation.

To investigate the relationship between Sox9 and ectopic cartilage formation, we reduced the Sox9 expression in mice lacking Adam19. Sox9-reduced mice did not show the ectopic cartilage formation. Conversely, Sox9-overexpressing mice formed ectopic cartilage in their hearts in the same manner as Adam19-deficient mice. These results suggest that ectopic cartilage formation is due to increased expression of the Sox9 gene in Adam19-deficient mice.

Since BMP signaling positively regulates Sox9 expression and ectopic cartilage formation was also reproduced in neural crest cell-specific Adam19-deficient mice, we hypothesized that Adam19 inhibits Sox9 expression by cleaving the BMP receptor in CNCCs.

Cultured cell experiments showed that Adam19 selectively cleaves one of the BMP receptors, Alk2 (Acvr1). To verify this result in living mice, we administrated an inhibitor of Alk2 / Alk3 to Adam19-deficient mice. The inhibitor treatment abolished a formation of ectopic cartilage in Adam19-deficient mice.

Overall, Adam19 expression in cardiac neural crest cells actively inhibits cartilage formation by suppressing the BMP-Sox9 signal pathway via Alk2 processing.

 

Graphical summary