Mechanisms Of Lineage-specific Gene Expression

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This project focuses on the transcription factors HB9 and BSAP, originally identified in B lymphocytes. The HB9 gene also referred to as HlxB9 encodes a homeodomain coding protein. Gene targeting in mice has revealed a critical role for HB9 in motor neuron and pancreas development. Abnormalities in the sacral region occurs in humans with one abnormal HB9 allele. Mice heterozygotic for an HB9 null mutation are normal, but mice that lack HB9 die at birth of respiratory failure due to a lack of diaphragm innervation. The motor neuron defects may arise from the inappropriate expression of genes normally expressed in other types of neurons. These mice also lack a portion of their pancreas, the dorsal lobe, and have reduced numbers of insulin producing beta cells in their residual ventral lobe. Because the developmental defects and perinatal lethality makes assesmment of the function of HB9 in adult tissues impossible, we have used a conditional gene targeting approach and have introduced loxP sites on either side of exon 3 of the HB9 gene. We have shown that the introduction of the LoxP sites does not interfere with normal HB9 expression. We have obtained MX-Cre transgenic mice, where the Cre recombinase can be induced by interferon treatment. We have introduced the MX-Cre transgene onto the HB9 loxP background. We have shown that the expression of Cre causes the deletion of exon 3 of HB9, but good deletion only occured in spleen, bone marrow, and intestine. In contrast, we found little deletion in the pancreas. We have found little effect on deleting HB9 in those tissues where Cre is expressed. To determine the consequences of deleting HB9 in the developing and adult pancrease we have crossed the HB9 Cre lox mice with mice expressing Cre from a transgene regulated by the insulin promoter. Mice in which HB9 exon 3 is flanked by loxP sites on both alleles and which express Cre from the insulin promoter should be available this fall for analysis. BSAP is a transcription factor critical for B-lymphocyte development and lineage committment. Mice overexpressing BSAP have B cells which are hyperproliferative, have an apoptosis defect, and a propensity for developing lymphomas. We have largely completed the analysis of these mice.