During limb development, expression of cathepsin D and B genes prefigure the pattern of interdigital apoptosis including the differences between the chick and the webbed digits of the duck. Expression of cathepsin L is associated with advanced stages of degeneration. Analysis of Gremlin-/- and Dkk-/- mouse mutants and local treatments with BMP proteins reveal that the expression of cathepsin B and D genes is regulated by BMP signaling, a pathway responsible for triggering cell death. Further cathepsin D protein is upregulated in the preapoptotic mesenchyme before being released into the cytosol, and overexpression of cathepsin D induces cell death in embryonic tissues by a mechanism including mitochondrial permeabilization and nuclear translocation of AIF. Combined inhibition of cathepsin and caspases suggests a redundancy in the apoptotic molecular machinery, providing evidence for compensatory activation mechanisms in the cathepsin pathway when caspases are blocked. It is concluded that lysosomal enzymes are functionally implicated in embryonic programmed cell death.
Bibliographical noteFunding Information:
Thanks are due to Montse Fernandez Calderon, Sonia Perez Mantecon and Maria Aramburu Landeras for technical assistance and to Dr. Aixa Morales for expression vectors. Antibodies, LEP100 and TAP1 were obtained from the Developmental Studies Hybridoma Bank, University of Iowa. This work was supported by grants from the Foundation BBVA and Ministerio de Educacion y Ciencia to JMH (BMC2002-02346) and from the G. Harold and Leila Y. Mathers Charitable Foundation and the National Institutes of Health to JCIB. JAM is supported by the Ramon y Cajal program from the Spanish Education and Sciences Ministry. VZL is supported by a grant from the Fundaçao para a Ciencia e a Tecnologia, Portugal (SFRH/BD/5834/2001).
- Interdigital cell death
- Limb development