Anti-apoptotic BCL-2 family members in development

Abstract

Almost 30 years ago it was first appreciated that anti-apoptotic B-cell lymphoma-2 (BCL-2) prevents the induction of apoptosis not only in malignant cells, but also in normal cellular lineages. This critical observation has rapidly evolved from merely identifying new BCL-2 family members to understanding how their biochemical interactions trigger the cell death process, and, more recently, to pharmacological inhibition of anti-apoptotic BCL-2 function in disease. Indeed, the proper regulation of apoptosis is important in many aspects of life including development, homeostasis, and disease biology. To better understand these processes, scientists have used many tools to assess the contribution of individual anti-apoptotic BCL-2 family members. This review will focus on the prominent roles for BCL-2 and other pro-survival family members in promoting the development of mammals during early embryogenesis, neurogenesis, and hematopoiesis.

Figure 1

Anti-apoptotic expression levels during pre-implantation embryonic development. Fertilized eggs, known as zygotes, express proteins encoded for by maternally inherited mRNAs. The activation of gene expression from the embryonic genome occurs following E2. Early embryos rapidly divide becoming a mass of cells, known as a morula by E2.5. At the 16 cell morula stage, some of the cells (indicated in brown) destined to become extraembryonic tissues (eg, placenta, amniotic sac, etc.) start to segregate to the periphery of the embryo whereas the others (indicated in yellow) that will become the embryo coalesce. Around E3.5, the embryo undergoes blastogenesis where the trophoblasts (brown) that will become the extraembryonic endoderm form a thin layer around an open cavity (blastocoel). The cells that will become the embryo form the inner cell mass (yellow). Around E4–4.5 the blastocyst implants in the uterus. Gene expression analysis from isolated embryos has revealed the relative expression patterns of individual anti-apoptotic BCL-2 family members. Indicated are the anti-apoptotic molecules that have been implicated in pre-implantation development and the color-coded bars indicate their relative expression and timing by stage and the tapering indicates increased or decreased expression accordingly

Figure 2

Anti-apoptotic BCL-2 family member roles during hematopoiesis. All hematopoiesis arises from a common HSC that is capable of self-renewal as well as generating multi-potent progenitors (MPPs). Driven by cues, the MPP gives rise to CMPs and CLPs. CMPs produce two more progenitor populations, the MEP and the GMP. MEPs produce the megakaryocytes, which give rise to platelets, as well as the erythroid lineage. The GMPs give rise to the granulocytic lineages including neutrophils as well as monocytes, which become macrophages. CLPs give rise to B and T lymphocytes and natural killer (NK) cells. Indicated are the anti-apoptotic BCL-2 family members that have been demonstrated to be required at each stage or in each differentiation process. If multiple family members have been implicated, the one with a less prominent role is flanked by parentheses. Stages for which no family member has been identified to critically promote survival are indicated with a question mark (?). Arrows demonstrate the developmental pathways, but are not meant to indicate direct differentiation as in many cases intermediate developmental stages have been identified