According to the concept of hierarchical cell differentiation somatic stem cells gradually lose their potential to self renew and to produce more than one tissue type. Recently, this concept has been challenged by the demonstration that cells from adult organs may be converted into other tissue types. This phenomenon termed plasticity applies to subsets of cells known as tissue stem cells (TSC). The biology of these TSC is generally poorly understood in part due to the paucity of markers. The overall long-term goal of this proposal is to contribute to a better understanding of the cell differentiation process by determining the role of BAALC, a novel gene, in cell biology. BAALC is expressed in all neuroectodermal tissues including brain tumors, in CD34 positive bone marrow progenitors, and in leukemic blasts from a subset of patients with acute leukemia. In acute myeloid leukemia with normal karyotype, high expression of BAALC independently predicts poor prognosis, suggesting a role in malignancy. To understand the function of BAALC, and to determine whether it serves as a marker both for neurogenic and hematopoietic stem cells and affects their biology, animal modeling in mice will be pursued. Because the structure of BAALC gives no hints about its function, a conventional knockout mouse will be created that will show whether BAALC is vital for embryonic development. Moreover, by examining mice deficient in BAALC it will be determined what cells are mainly affected and at what developmental stage BAALC exerts its function. To specifically determine BAALC's role in neuropoiesis and hematopoiesis conditional, tissue-specific Baalc knockout mice will be generated using the Cre/IoxP recombination technology. These mice will provide insight into Baalc's role in neuropoiesis and hematopoiesis in vivo even in case the conventional knockout condition turns out to be lethal. The mice will be studied immunohistochemically, and by applying various cell lineage-, time-, and developmental stage-specific markers. It is postulated that the high degree of evolutionary conservation of BAALC in mammals will allow observations in mice to be applicable to humans.
