Abl and Arg nonreceptor tyrosine kinases are widely expressed in mammals, where they contribute to the development of diverse organ and tissue systems. Deletion of abl or arg in mice reveals roles for the kinases in B and T lymphocyte development, neurulation, neuronal dendrite maintenance, synaptic plasticity, and osteoblast development. Double knockout abl^-/-arg^-/- mice die as embryos, indicating that Abl and Arg also perform essential and overlapping functions during embryonic development. Abl and Arg contain domains for protein-protein interactions (SH3, SH2, proline-rich sequences, PY sequences), cytoskeleton binding (filamentous actin and microtubule binding domains), nuclear translocation (nuclear localization and export sequences), and DNA binding. Although a full understanding of their molecular interactions is still forthcoming, it is clear that Abl and Arg provide many cell types with all-in-one multifunctional signaling tools that serve as links between the cell surface and downstream pathways to both the cytoskeleton and nucleus.

Introduction

The mammalian Abl nonreceptor tyrosine kinase family consists of Abl and Arg (Abl-related gene, also called Abl2). c-abl was identified as the cellular (c for cellular) homologue of v-abl (v for viral), the transforming gene of the Abelson murine leukemia virus (AMulV), and encodes the nonreceptor tyrosine kinase Abl.^1-3 c-abl (hereafter abl) was later shown to be involved in human leukemias due to a chromosomal translocation resulting in fusion of N-terminal sequences of Bcr to abl, causing formation of the Philadelphia chromosome and Bcr-abl oncogenes.² Bcr-abl tyrosine kinases are constitutively active and transform lymphoid cells in culture and in mice.⁴ Because of the involvement of abl in malignancy, a search for related genes was performed (actually using c-DNA probes to v-abl) and the abl-related gene (arg) was identified.^5,6

Abl and Arg share extensive sequence and structural similarity (fig. 1). Both have two predominant alternatively spliced forms, in mice designated Abl type I and IV and Arg type 1a and 1b, each containing one of two different first exons and resulting in distinct N-terminal peptide sequences.^5,7,8 The biological functions of each isoform remains unclear, although a few reports have documented differences in requirements for type I and type IV Abl in mediating differentiation or survival in response to lipopolysaccharide (LPS) treatment of lymphoid cell lines.^9,10 However, either Abl isoform can complement the lymphocyte defects (see below) of abl mutant mice when expressed as transgenes.¹¹ Following the N-terminal domain, Abl and Arg contain Src homology 3 (SH3), Src homology 2 (SH2) protein interaction domains and tyrosine kinase domains. They contain three conserved PXXP motifs C-terminal to the kinase domain that serve as potential binding sites for SH3 domain-containing proteins.¹² The near 90% identity in their N-terminal halves suggests that Abl and Arg have common interactors or substrates, and may share some cellular functions.

Figure 1

Domain structures of Abl and Arg. Abl and Arg each have two alternatively spliced first exons resulting in two expressed isoforms, Abl type I and IV, and Arg type 1a and 1b. Abl and Arg contain SH3 (3), SH2 (2) and kinase domains; these domains are 89%, (more...)

Abl and Arg also contain cytoskeleton-binding domains in their C-terminal halves, features unique among nonreceptor tyrosine kinases. These consist of filamentous (F)-actin binding domains in Abl and Arg^13-15 (M. Krishnaswami and A.J. Koleske, unpublished data), and a microtubule (MT) binding domain in Arg.¹⁶ These domains localize Abl and Arg within the cell, and allow them to physically regulate actin and microtubule organization. Finally, Abl has three nuclear localization sequences (NLS)^17,18 and a nuclear export sequence (NES)¹⁹ that are absent in Arg. These domains allow Abl to shuttle between the cytoplasm and the nucleus in response to various stimuli. A DNA binding domain identified in Abl⁶⁸ currently has unknown physiological function.

One look at the lengthy list of functional domains present in Abl and Arg suggests that their molecular interactors are numerous and their physiological functions complicated. Add to that the wide tissue expression pattern of Abl and Arg (see below), and it becomes clear that understanding their roles in development would not be easy. This has proven true. Since the generation of abl mutant mice nearly 15 years ago, how Abl kinases contribute to mammalian development has been and continues to be the subject of intense study. Mice lacking the second mammalian Abl family kinase member, Arg, were subsequently engineered and analysis of their phenotypes gives insight into the unique roles the kinases play during development. Examination of these mutant mice demonstrates that Abl and Arg participate in a wide and seemingly unrelated variety of developmental processes, and that Abl and Arg possess both shared and unique functions.

In this chapter, I review the developmental processes that require Abl and Arg function in mammals (mostly mice), which include lymphocyte development, neuronal development, and bone development. The diversity of these processes makes it impossible to thoroughly discuss every aspect of the signaling that regulates them. Therefore, in considering how Abl and Arg may participate in these molecular pathways, I attempted to focus on data obtained from experiments using primary tissues or cells, with the assumption that these results provide the best insight into the normal functions of the kinases. From this survey, it becomes clear that Abl and Arg are multifunctional tools with many features cells find useful. Cells of many types employ these functions for their specific cellular tasks. In this way, Abl and Arg are recruited to participate in signaling to transduce information from a wide variety of cell surface receptors to both the cytoskeleton and the nucleus.

Tissue Expression Patterns of Abl and Arg

Overlapping patterns of Abl and Arg expression are detected in many cell types and tissues, although the level of Abl expression may be quite different from that of Arg in a given tissue. In addition, their expression levels can vary substantially from tissue to tissue, and may change during the course of normal development. Abl is expressed in a wide range of mouse tissues, including the spleen, thymus and brain.^20-22 Abl can be isolated in purified synaptosomes from mouse brain.²³ Of adult human tissues, Abl is found in small mucous glands and ductules, gastric crypts, endocervix, ovarian follicles, breast myoepithelium, prostatic acini, renal tubules, transitional epithelium, skin adnexae, myeloid cells and osteoblasts.²⁴ In contrast to data obtained from mouse, no Abl is detected in human cerebral cortical neurons, lymph nodes or spleen.²⁴ Human fetal tissues show a similar expression pattern to the adult, with additional expression in squamous mucosa, sex cords, adrenal cortex and medulla, small intestinal and colonic epithelium, skeletal, cardiac and smooth muscle, capillary endothelial cells and endocardial intima. Strong expression is also observed in osteoblasts and their associated neovasculature in sites of endochondral ossification.²⁴

Arg expression is highest in the brain, with significant levels also found in spleen, thymus and muscle tissue.^21,25 Arg is particularly concentrated in synapse-rich brain regions, and localizes to dendritic spines and to purified synaptosomes in adult mice.^21,26 Embryonic mice have high levels of both Abl and Arg in the developing neuroepithelium.²¹ The variety of tissues expressing Abl and Arg suggests that many cellular processes and signaling pathways utilize these kinases to carry out their functions.

Deletion of abl and arg in Mice Reveals Essential Roles for the Kinases

Two c-abl mutant alleles were designed and utilized to engineer mice lacking Abl function. abl² (hereafter abl^-) is a true null allele, and no Abl protein is detected in abl² homozygous (abl^-/-) mice.²⁷ A second allele, designated abl^m1, eliminates the C-terminal one-third of Abl containing its DNA-binding and cytoskeleton-binding domains, but retains the N-terminal portion containing the SH3, SH2 and kinase domains, 3 proline-rich regions adjacent to the kinase domain, and NLS sequences.^28-30 Approximately 75% of abl^-/- and abl^m1/m1 mice are runted and die within the first two weeks after birth. The remaining 25% of abl^-/- and abl^m1/m1 mutants are highly susceptible to infections throughout life, such as pneumonia, gastroenteritis and infections of the nasal passages and ears.^27,28 The cause of increased susceptibility to infection in these mice remains to be demonstrated.

Homozygous mutant mice expressing a null allele of arg are strikingly healthy and robust compared to abl mutant mice.²¹ Although arg^-/- pups are runted at 3 weeks of age, by 6 weeks they are similar in weight to wild type littermates. arg^-/- mice are born at expected Mendelian ratios, and survive to healthy adulthood.21 Loss of Arg does not result in immune deficiency as seen in abl mutants.

Intercrosses of abl and arg mutants reveal overlapping roles for Abl and Arg during development.²¹ While abl^+/-arg^+/- mice are born and survive in expected Mendelian ratios, only 60% of abl^+/-arg^-/- mice survive to adulthood. abl^-/-arg^+/- mice die embryonically at 15.5 days post-coitum (dpc) and display pericardial sac and peritoneal hemorrhaging. abl^-/-arg^-/- mice are most severely affected and die as embryos at 10.5 dpc. Internal bleeding in the pericardial sac is also observed in these embryos, and likely results in their early death.²¹ However, the cellular and molecular defects that result in death of abl^-/-arg^-/- and abl^-/-arg^+/- embryos are yet unknown. Immunostaining revealed Abl expression in cardiac muscles of human fetuses,²⁴ suggesting that heart development or function may require Abl and Arg. Alternatively, deletion of Abl and Arg may slightly compromise the development of several systems, which when combined fail to support the life of the embryo.

Lymphocyte Development in abl^-/- and abl^m1/m1 Mice

B and T Cell Development Require Abl

The bone marrow and thymus are the major sites for early development of the immune system's B and T lymphocytes, respectively. These organs provide both soluble and cell-anchored stromal signals that direct lymphocyte development, and as such, their unique environments are critical to the development of the immune system. Once they have completed their developmental programs there, naïve B and T lymphocytes leave the bone marrow and thymus, homing to peripheral lymphoid organs including the spleen and lymph nodes, where they complete their maturation and may become activated upon encountering antigen. As B and T cells work closely together to protect the body from invasion, both must properly develop and migrate in order for these cells to be available throughout the body to recognize and eliminate foreign antigens.

The increased susceptibility to infection of the abl^-/- and abl^m1/m1 mice suggested that these mutants have defects in immune development or function. Indeed, similar (but not identical) phenotypes of reduced total B and T cell numbers are observed in abl^-/- and abl^m1/m1 mutants.^27,28,31 Consistent with this finding, abl^-/- and abl^m1/m1 mutant mice display a reduced size and cellularity of the thymus. Atrophy of the spleen is also observed, but is less severe than reductions in the thymus. In abl^m1/m1 mice, spleens exhibit an abnormal short, squatty shape with rounded edges, instead of the normal elongated knife-blade shape.²⁸

Lymphocytes express specific combinations of immunoglobulin and other cell surface receptors as they progress through development. The combination of receptors serves as a means to identify populations of cells in specific developmental stages. For B cells, the developmental program progresses though pro-B, pre-B, and immature B stages before reaching the mature B stage capable of responding to antigens (Table 1). When examined by flow cytometry for stage-specific markers, adult abl^m1/m1 mice exhibit reductions in bone marrow-derived early B cell classes, including pro-B, pre-B and immature B cells (Table 1).^28,31 On average, total B cells from bone marrow are reduced to 67% of control B cell numbers, with more severe reductions in pre-B cells relative to pro-B cells.³¹ In general, B cell depletion is less severe in spleen compared to bone marrow, and abl^m1/m1 mutants exhibit at worst a 19% reduction in splenic B cells. Interestingly, circulating mature B cells in peripheral blood are nearly normal in abl^m1/m1 mice, suggesting that the defect in early B cell development may be overcome in later stages of development.

The thymi of newborn abl^m1/m1 mice contain on average only one-third the number of cells found in those of control littermates, although the relative proportions of immature and mature T cells appear to be normal in these mutants. In contrast to the reduction in thymic T cells, the number of circulating mature T cells in peripheral blood is only slightly reduced, similar to the effect seen in B cells.²⁸ Splenic T cells are normal or elevated in abl^m1/m1 mice. Thus, T cell development is less severely affected by the abl^m1> mutation than B cell development.

Like abl^m1/m1 mutants, abl^-/- mice exhibit reductions in both B and T cell numbers.²⁷ Early B cell classes are reduced in abl^-/- bone marrow, while mature B cells are present at normal levels relative to animal body weight. However, in contrast to abl^m1/m1 animals, reductions in total peripheral lymphocyte numbers to 73% of wild type levels are observed in 3 to 5 week old abl^-/- mice. Deficiencies in both B and T cell populations contribute to this reduction; however, the specific populations of B or T cells affected has not been determined. Thus, very similar lymphocytic phenotypes are observed in two different abl mutants, providing solid evidence that Abl function contributes to the development of B and T lymphocytes.

Table 1

Average percentage of B cells in abl^m1/m1 relative to control mice.

Does Arg contribute to lymphocyte development? Unlike abl mutants, no defects are observed in arg^-/- lymphocyte numbers from bone marrow, thymus, spleen or peripheral blood.²¹ A recent report raises the possibility that Arg cannot functionally compensate for Abl during early B cell development because its expression is low during pro-B and pre-B cell stages when defects are most severe in abl mutants, and only later increases in mature B cells.³² However, because abl^-/-arg^-/- mice die as embryos before significant lymphopoeisis take place, whether Arg and Abl serve redundant functions in lymphocyte development remains unknown.

Interleukin-7, B Cell Receptor, and T Cell Receptor Signaling through Abl

Several studies suggest that Abl helps to mediate interleukin-7 (IL-7) signaling, providing an attractive mechanism to explain many of the observed lymphopoeisis defects in abl mutant mice (fig. 2A). IL-7 is a stromal cell-derived cytokine critical for early bone marrow B cell development in mice. Similar to abl mutants, mice lacking IL-7 either through genetic deletion or treatment with anti-IL-7 antibodies display defects in early lymphopoeisis (pro-B cell stage)^33,34 and consequent lymphopenia.35 IL-7 stimulates proliferation of pro-B cells in vitro and in vivo.^36-38 This proliferative response to IL-7 is reduced in abl^m1/m1 bone marrow colony formation cultures relative to wild type cultures, although IL-7-induced proliferation of abl^m1/m1 cells in liquid culture is normal.³¹ These observations suggest that IL-7-stimulated pro-B cell proliferation in bone marrow requires Abl function.

Figure 2

Hypothetical model for Abl regulation of B lymphocyte development. A) Abl may mediate signals from the IL-7 receptor (IL-7R). During the pro-B and pre-B cell stages, IL-7 signals activate JAK1, JAK3, STAT5 and STAT6, leading to proliferation and cell (more...)

Further support for this hypothesis comes from studies of the activated v-Abl kinase expressed AMulV-transformed cells. AMulV specifically transforms lymphoid precursors, including pro-B and pre-B cells, rendering their growth IL-7 independent.³⁹ Pre-B cells expressing v-Abl exhibit constitutively activated Janus protein kinase 1 (JAK1), JAK3, STAT5 and STAT6, critical elements of IL-7 signal transduction in pre-B cells.^40,41 Conversely, IL-7 treatment can reconstitute some v-Abl-mediated activities when v-Abl is acutely inactivated in transformed pre-B cells.⁴² These results demonstrate that an activated Abl kinase deregulates and activates IL-7 signaling, leading to IL-7 independent, uncontrolled proliferation. Like expression of v-Abl, transgenic or exogenous IL-7 administration contributes to B lymphoid transformation.^43,44 It will be of interest to determine whether exogenous administration or transgenic IL-7 can overcome the lymphopenia of abl mutants.

Both abl^m1/m1 and IL-7^-/- B cells also exhibit increased apoptosis, which may contribute to the observed reduction in pro-B and pre-B cells in mutant bone marrow.^45,46 Interestingly, whereas IL-7 withdrawal from wild type progenitor B-cell lines results in G1 arrest, it promotes apoptosis in abl^m1/m1 B-cell lines.^45,47 Furthermore, as IL-7 and v-Abl have been shown to positively regulate the levels of antiapoptotic proteins Bcl-2 and Bcl-x_L,⁴² loss of Abl signaling may result in reduced levels of Bcl-2 and/or Bcl-x_L leading to increased apoptosis. Thus, Abl may mediate pro-survival signaling from the IL-7 receptor in bone marrow pro-B and pre-B cells.

Once B cells complete their development in the bone marrow, some will migrate to the spleen, where their survival and maintenance requires signals from the B cell receptor (BCR).⁴⁸ Interestingly, a recent study reports that abl^-/- splenic B cells are deficient in their proliferative response to BCR stimulation, suggesting that depletion of B cells in the spleen of abl mutants may result from specific defects in the signaling pathway activated by BCR stimulation.⁴⁹ Abl associates with and phosphorylates the BCR coreceptor CD19, which serves to activate downstream components of BCR signaling by recruiting effector proteins such as Syk and Btk.^49,50 These data suggest that Abl and CD19 act in a similar signaling pathway that modulates BCR-mediated splenic B cell proliferation (fig.2B).

What about T cells? abl^m1/m1 and abl^-/- mice display reductions in T cell numbers in the thymus and peripheral blood, respectively.^27,28 Treatment of chronic myelogenous leukemia (CML), a disease caused by expression of the activated Bcr-abl protein in myeloid cells, with the specific Abl and Arg kinase inhibitor STI-571 (imatinib mesylate or Gleevec), has recently prompted investigation of the effects of Abl inhibition on T cell proliferation. Even though T cells from CML patients do not express the STI-571 target Bcr-abl, their proliferation is inhibited in a dose-dependent manner by STI-571,^51,52 suggesting that Abl is required for the normal proliferation of T cells. In particular, T cell receptor (TCR)-mediated T cell proliferation is blocked by STI-571.^53,54 Importantly, recent work demonstrates that TCR stimulation activates Abl to phosphorylate Zap70 and the linker for activation of T cells (LAT), effectors of TCR signaling that lead to transcription and eventual production of the cytokine IL-2.⁵³ Thus, Abl can phosphorylate two downstream effectors of the TCR to stimulate a T cell proliferation pathway.

Neuronal Development in abl^-/- and arg^-/- Mice

Bone Development in abl^-/- Mice

Consistent with the high expression level of Abl in osteoblasts of human fetuses,²⁴ abl^-/- mice have osteoporosis, displaying thinner bone volume and bone mineral content than wild type mice.⁶⁴ Thinning of bone volume may be due to increased bone absorption by osteoclasts or reduced bone deposition by osteoblasts. Therefore, proper development and function of osteoclasts and osteoblasts is critical for bone development and maintenance. Osteoclastogenesis and osteoclast function are normal in abl^-/- mice, but by several measures, osteoblastogenesis is delayed or defective during early maturation.⁶⁴ This leads to a dramatically reduced rate of bone mineral deposition in abl^-/- mice.

Bone development is probably the least understood of all abl mutant phenotypes. There have been no further studies on Abl regulation of osteoblast development, or any reports of whether Arg may contribute to this process. Li et al⁶⁴ speculate that Abl may participate in extracellular matrix (ECM)-integrin signaling in osteoblasts, a critical pathway in osteoblast differentiation. This hypothesis is supported by the finding that Abl kinase activity increases upon fibroblast adhesion to the ECM protein fibronectin,⁶⁵ and by our work demonstrating that Abl mediates integrin signaling in neurons.⁶⁰

Conclusion

The study of abl and arg mutant mice has certainly advanced our understanding of the normal functions of Abl and Arg. We now know that Abl and Arg participate in a wide variety of developmental processes. However, we have yet to fully understand the molecular mechanisms the kinases use to regulate these processes. In addition, the molecular basis of overlapping versus distinct functions of Abl and Arg in specific processes is unknown. Many mutant phenotypes occur with variable penetrance and severity. This has been noted for several aspects of lymphocyte development,^27,28,31,55 as well as bone development,⁶⁴ but its cause also remains unknown. Future work will undoubtedly shed light on these questions.

There seems to be no rhyme or reason to the group of tissue systems in which Abl and Arg function during development, except that in each developmental event, Abl and Arg have been utilized by a specialized cell type for a specific signaling need. For Abl and Arg, these range from pathways promoting cell proliferation and survival to cytoskeletal regulation. Clearly, with the versatility of a Swiss Army knife, Abl and Arg are perfectly suited for this multi-tasking.

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