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Retinoic acid regulates programmed cell death through BMP signalling

Nature Cell Biology volume 1, pages 125–126 (1999)Cite this article

Programmed cell death by apoptosis is one of the major driving forces that shape and pattern the organs and tissues of a developing embryo. One of the best model systems for the study of apoptosis is the interdigital cell death (INZ) that occurs during the outgrowth of the vertebrate limb. However, although much has been learned about the cells involved in this process1, the molecular mechanisms underlying INZ remain unclear. Retinoic acid (RA)2,3 and bone morphogenetic proteins (BMPs)4,5,6 are two of the signalling components known to be involved in INZ. However, the exact relationships between these two factors in controlling cell death remain unknown. Here we show that RA can control INZ by promoting BMP gene expression and simultaneously repressing the chondrogenic potential of BMPs.

In addition to its inhibitory effect on INZ, RAA treatment was followed by formation of extra digits (Fig. 1k) and thickening of the phalanges adjacent to the treated interdigit (23% of increased diameter evaluated in whole-mount cartilage-stained specimens; P < 0.001 when analysed by ANOVA/Bonferroni tests, Fig. 1i,j). This suggested an additional function for RA as an inhibitor of chondrogenesis. This hypothesis was tested by implanting RA-beads at the tip of digit III, which resulted in the accumulation of undifferentiated msx-expressing cells (msx-1 and msx-2; Fig. 1l,m), and subsequent massive apoptosis (Fig. 1n) which led to digit truncation (Fig. 1o,p). In agreement with this result, interdigital expression of msx genes was considerably downregulated after implantation of RAA-beads in the interdigital space ( Fig. 1q,r). Molecular markers of the growing tips of the digits7 were not initially downregulated by implantation of RA beads at the tips, but remained confined to the more proximal mesoderm which had already undergone chondrogenic differentiation (expressing tgfβ 2, β a-activin and bmpR1b, not shown). Because BMPs promote chondrogenesis7,10 in addition to apoptosis, these results reflect a complementary function for RA in repressing chondrogenesis by interdigital BMPs through RA-mediated upregulation of msx genes. These genes are characteristic markers of the undifferentiated limb mesoderm and expression of msx-2 is required for the apoptosis-promoting effect of BMPs11,12. Thus, the downregulation of msx-2 expression by RAA reinforces the relationship between RA and BMPs in the control of interdigital cell death. Other functions previously proposed for RA in the regression of the interdigital web3 of the mouse need not be discarded; these include the regulation of proteases involved in the degradation of the extracellular matrix and the regulation of enzymes potentially involved in cellular changes associated with apoptosis. In fact, syndactyly is a frequent finding in mutant mice with genetic alterations in the nuclear receptors for RA13,14 suggesting a wide spectrum of functions for RA during interdigital tissue regression. In conclusion, our results unravel a mechanism by which RA in conjunction with BMPs might regulate programmed cell death. It is worth noting the existence of other developmental systems (for example, neural crest cells of the rhombencephalic segments11), where apoptosis can be influenced by RA15 and correlates with the expression of msx and bmp genes. Hence, our results suggest that the molecular pathway described here might be a general apoptotic regulatory mechanism that is used time and again in the sculpturing and patterning of a variety of organs and tissues during embryogenesis.

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Figure 1: Effect of retinoic acid (RA) and retinoic acid antagonist (RAA) on chick limb development.

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Acknowledgements

This work was supported by grants from the DGICYT (to J.M.H. and Y.G.) RAA was kindly provided by R.A.S. Chandraratua; Noggin and Gremlin were provided by Regeneron Pharmaceuticals Inc.

Correspondence and requests for materials should be addressed to J.M.H..

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Authors and Affiliations

  1. Departamento de Ciencias Morfológicas y Biología Animal y Celular, Universidad de Extremadura, Badajoz, 06071, Spain

    J. Rodriguez-Leon, D. Macias & Y. Gañan

  2. Departamento de Anatomía y Biología Celular Universidad de Cantabria, Santander, 39011, Spain

    R. Merino, E. Santesteban & J. M. Hurle

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  1. J. Rodriguez-Leon
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Correspondence to J. M. Hurle.

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Rodriguez-Leon, J., Merino, R., Macias, D. et al. Retinoic acid regulates programmed cell death through BMP signalling . Nat Cell Biol 1, 125–126 (1999). https://doi.org/10.1038/10098

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