Abstract
Bcl-2 functions as a death repressor molecule in an evolutionarily conserved cell death pathway. To further explore the role of Bcl-2 in development, we assessed its pattern of expression during murine embryogenesis. Immunohistochemical analysis demonstrates that Bcl-2 is widely expressed early in mouse fetal development in tissues derived from all three germ layers and that this expression becomes restricted with maturation. Within epithelium, the E12.5 lung bud demonstrates a proximal to distal gradient of Bcl-2 expression which is enhanced by E18.5. Bcl-2 is expressed throughout the intestinal epithelium through E14.5, but by E18.5 only cells in the crypts and lower villi express Bcl-2. In the mesoderm-derived kidney, Bcl-2 is expressed in both the ureteric bud and metanephric cap tissue at E12.5. Tubular structures also express Bcl-2, although overall levels drop as the kidney matures. Retinal neuroepithelial cells uniformly express Bcl-2 until cells begin to differentiate and then display the topographic distribution maintained into adulthood. The developing limb provides a clear example where Bcl-2 is restricted to zones of cell survival; Bcl-2 is expressed in the digital zones but not in the interdigital zones of cell death. The wide distribution of Bcl-2 in the developing mouse suggests that many immature cells require a death repressor molecule or that Bcl-2 may have roles beyond regulating developmental cell death.
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Selected References
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- Alnemri E. S., Robertson N. M., Fernandes T. F., Croce C. M., Litwack G. Overexpressed full-length human BCL2 extends the survival of baculovirus-infected Sf9 insect cells. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7295–7299. doi: 10.1073/pnas.89.16.7295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
- Chang G. Q., Hao Y., Wong F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron. 1993 Oct;11(4):595–605. doi: 10.1016/0896-6273(93)90072-y. [DOI] [PubMed] [Google Scholar]
- Chen-Levy Z., Nourse J., Cleary M. L. The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation. Mol Cell Biol. 1989 Feb;9(2):701–710. doi: 10.1128/mcb.9.2.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cleary M. L., Smith S. D., Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 1986 Oct 10;47(1):19–28. doi: 10.1016/0092-8674(86)90362-4. [DOI] [PubMed] [Google Scholar]
- Coles H. S., Burne J. F., Raff M. C. Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development. 1993 Jul;118(3):777–784. doi: 10.1242/dev.118.3.777. [DOI] [PubMed] [Google Scholar]
- Graninger W. B., Seto M., Boutain B., Goldman P., Korsmeyer S. J. Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. J Clin Invest. 1987 Nov;80(5):1512–1515. doi: 10.1172/JCI113235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hockenbery D. M., Oltvai Z. N., Yin X. M., Milliman C. L., Korsmeyer S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. doi: 10.1016/0092-8674(93)80066-n. [DOI] [PubMed] [Google Scholar]
- Hockenbery D. M., Zutter M., Hickey W., Nahm M., Korsmeyer S. J. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961–6965. doi: 10.1073/pnas.88.16.6961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
- Hurle J. M., Fernandez-Teran M. A. Fine structure of the interdigital membranes during the morphogenesis of the digits of the webbed foot of the duck embryo. J Embryol Exp Morphol. 1984 Feb;79:201–210. [PubMed] [Google Scholar]
- Hurle J. M., Fernandez-Teran M. A. Fine structure of the regressing interdigital membranes during the formation of the digits of the chick embryo leg bud. J Embryol Exp Morphol. 1983 Dec;78:195–209. [PubMed] [Google Scholar]
- Hurle J. M., Gañan Y. Interdigital tissue chondrogenesis induced by surgical removal of the ectoderm in the embryonic chick leg bud. J Embryol Exp Morphol. 1986 Jun;94:231–244. [PubMed] [Google Scholar]
- Jacobson M. D., Burne J. F., King M. P., Miyashita T., Reed J. C., Raff M. C. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature. 1993 Jan 28;361(6410):365–369. doi: 10.1038/361365a0. [DOI] [PubMed] [Google Scholar]
- Jiang T. X., Yi J. R., Ying S. Y., Chuong C. M. Activin enhances chondrogenesis of limb bud cells: stimulation of precartilaginous mesenchymal condensations and expression of NCAM. Dev Biol. 1993 Feb;155(2):545–557. doi: 10.1006/dbio.1993.1051. [DOI] [PubMed] [Google Scholar]
- Kane D. J., Sarafian T. A., Anton R., Hahn H., Gralla E. B., Valentine J. S., Ord T., Bredesen D. E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. doi: 10.1126/science.8235659. [DOI] [PubMed] [Google Scholar]
- Koseki C., Herzlinger D., al-Awqati Q. Apoptosis in metanephric development. J Cell Biol. 1992 Dec;119(5):1327–1333. doi: 10.1083/jcb.119.5.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kozopas K. M., Yang T., Buchan H. L., Zhou P., Craig R. W. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3516–3520. doi: 10.1073/pnas.90.8.3516. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LeBrun D. P., Warnke R. A., Cleary M. L. Expression of bcl-2 in fetal tissues suggests a role in morphogenesis. Am J Pathol. 1993 Mar;142(3):743–753. [PMC free article] [PubMed] [Google Scholar]
- Lin E. Y., Orlofsky A., Berger M. S., Prystowsky M. B. Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J Immunol. 1993 Aug 15;151(4):1979–1988. [PubMed] [Google Scholar]
- Linden R., Serfaty C. A. Evidence for differential effects of terminal and dendritic competition upon developmental neuronal death in the retina. Neuroscience. 1985 Jul;15(3):853–868. doi: 10.1016/0306-4522(85)90083-1. [DOI] [PubMed] [Google Scholar]
- McDonnell T. J., Korsmeyer S. J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature. 1991 Jan 17;349(6306):254–256. doi: 10.1038/349254a0. [DOI] [PubMed] [Google Scholar]
- McDonnell T. J., Nunez G., Platt F. M., Hockenberry D., London L., McKearn J. P., Korsmeyer S. J. Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population. Mol Cell Biol. 1990 May;10(5):1901–1907. doi: 10.1128/mcb.10.5.1901. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Merino R., Ding L., Veis D. J., Korsmeyer S. J., Nuñez G. Developmental regulation of the Bcl-2 protein and susceptibility to cell death in B lymphocytes. EMBO J. 1994 Feb 1;13(3):683–691. doi: 10.1002/j.1460-2075.1994.tb06307.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Merry D. E., Veis D. J., Hickey W. F., Korsmeyer S. J. bcl-2 protein expression is widespread in the developing nervous system and retained in the adult PNS. Development. 1994 Feb;120(2):301–311. doi: 10.1242/dev.120.2.301. [DOI] [PubMed] [Google Scholar]
- Michaelson J. Cell selection in development. Biol Rev Camb Philos Soc. 1987 May;62(2):115–139. doi: 10.1111/j.1469-185x.1987.tb01264.x. [DOI] [PubMed] [Google Scholar]
- Monaghan P., Robertson D., Amos T. A., Dyer M. J., Mason D. Y., Greaves M. F. Ultrastructural localization of bcl-2 protein. J Histochem Cytochem. 1992 Dec;40(12):1819–1825. doi: 10.1177/40.12.1453000. [DOI] [PubMed] [Google Scholar]
- Nuñez G., London L., Hockenbery D., Alexander M., McKearn J. P., Korsmeyer S. J. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed] [Google Scholar]
- Pezzella F., Tse A. G., Cordell J. L., Pulford K. A., Gatter K. C., Mason D. Y. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [PMC free article] [PubMed] [Google Scholar]
- Provis J. M. Patterns of cell death in the ganglion cell layer of the human fetal retina. J Comp Neurol. 1987 May 8;259(2):237–246. doi: 10.1002/cne.902590205. [DOI] [PubMed] [Google Scholar]
- Robinson S. R. Cell death in the inner and outer nuclear layers of the developing cat retina. J Comp Neurol. 1988 Jan 22;267(4):507–515. doi: 10.1002/cne.902670405. [DOI] [PubMed] [Google Scholar]
- Saxén L., Sariola H. Early organogenesis of the kidney. Pediatr Nephrol. 1987 Jul;1(3):385–392. doi: 10.1007/BF00849241. [DOI] [PubMed] [Google Scholar]
- Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
- Seto M., Jaeger U., Hockett R. D., Graninger W., Bennett S., Goldman P., Korsmeyer S. J. Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. EMBO J. 1988 Jan;7(1):123–131. doi: 10.1002/j.1460-2075.1988.tb02791.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spira A., Hudy S., Hannah R. Ectopic photoreceptor cells and cell death in the developing rat retina. Anat Embryol (Berl) 1984;169(3):293–301. doi: 10.1007/BF00315634. [DOI] [PubMed] [Google Scholar]
- Strasser A., Harris A. W., Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. doi: 10.1016/0092-8674(91)90362-3. [DOI] [PubMed] [Google Scholar]
- Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
- Vaux D. L., Weissman I. L., Kim S. K. Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science. 1992 Dec 18;258(5090):1955–1957. doi: 10.1126/science.1470921. [DOI] [PubMed] [Google Scholar]
- Veis D. J., Sentman C. L., Bach E. A., Korsmeyer S. J. Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J Immunol. 1993 Sep 1;151(5):2546–2554. [PubMed] [Google Scholar]
- Veis D. J., Sorenson C. M., Shutter J. R., Korsmeyer S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993 Oct 22;75(2):229–240. doi: 10.1016/0092-8674(93)80065-m. [DOI] [PubMed] [Google Scholar]
- Young R. W. Cell death during differentiation of the retina in the mouse. J Comp Neurol. 1984 Nov 1;229(3):362–373. doi: 10.1002/cne.902290307. [DOI] [PubMed] [Google Scholar]
- Yu H., Bauer B., Lipke G. K., Phillips R. L., Van Zant G. Apoptosis and hematopoiesis in murine fetal liver. Blood. 1993 Jan 15;81(2):373–384. [PubMed] [Google Scholar]