Critical Roles of Abl Family Tyrosine Kinases in Brain and Heart Development

The Abl family non-receptor tyrosine kinases, consisting of vertebrate c-Abl (Abl) and Arg (Abl-related gene, Arg), have been implicated in the development of several mammalian organ systems, including the immune system and bone. However, their functions in the development of brain and heart are poorly understood. Here, we generate an Abl conditional allele and show that targeted deletion of Abl in the developing brain on an Arg knockout background leads to motor coordination deficits and striking cerebellar malformations, including defects in anterior cerebellar morphogenesis, granule cell ectopia, and hypoplasia. Time course analyses reveal that the abnormal anterior cerebellar foliation results from local disruptions of the basement membrane located between radial glial endfeet and meninges during embryonic cerebellar development. Granule cell ectopia and hypoplasia are also associated with the breaches in the basement membrane and abnormal Bergmann glial networks during postnatal cerebellar development. In vitro culture experiments indicate that Abl/Arg-deficient granule cells can interact with glial processes, and proliferate normally in response to sonic hedgehog (Shh) compared to cells isolated from control mice. Consistent with these findings, selective ablation of Abl family kinases in cerebellar granule cells alone does not cause any abnormality, suggesting that deletion of Abl/Arg from glia is likely required for the mutant phenotype. Together, these results provide compelling evidence that Abl and Arg play key redundant roles in basement membrane maintenance and cortical lamination in the cerebellum. In another set of experiments, we demonstrate that Abl-/- embryos and newborns on the C57BL/6J background, but not on other tested backgrounds, exhibit strikingly enlarged hearts and die around birth. The heart defects can be largely rescued by cardiomyocyte-specific restoration of the full-length c-Abl protein. The cardiac hyperplasia is not due to decreased apoptosis, but rather to excessive cardiomyocyte proliferation during later stages of embryogenesis. Genes involved in cardiac stress and remodeling and cell cycle regulation are also up-regulated in Abl-/- hearts. These observations indicate a critical role for c-Abl in mammalian heart growth and development. In conclusion, our studies reveal that Abl family kinases are required for the development of cerebellum and heart, which might involve their roles in the regulation of actin cytoskeleton and cell proliferation, respectively.