This project focuses on the transcription factors HB9 and BSAP, originally identified as having important roles in B cell activation. During the past year we analyzed HB9 expression during embryonic development and the phenotype of HB9-/- mice. HB9 is an alanine rich homeodomain factor, which is expressed in activated B-lymphocytes, hematopoietic progenitors, pancreas, and developing motor neurons. HB9 deficient mice die at birth because they lack a phrenic nerve, and are unable to breathe. HB9 is critical for distinguishing the identity of motor neurons and interneurons specified by sonic hedgehog. During embryonic development sonic hedgehog specifies the identity of both motor neurons and interneurons. As progenitor cells in mice become committed to a motor neuron fate they begin to express HB9, whereas interneurons do not. Mice deficient in HB9 inappropriately express interneuron specific genes in motor neurons. This dysregulation in gene expression results in severe motor neuron axon pathfinding defects and disorganized topology within the spinal cord. Thus, motor neurons actively suppress genetic programs for interneurons to establish their identity. HB9 is also critical for the development of the dorsal lobe of the pancreas and for normal numbers of beta cells. The dorsal epithelium of the fore- and midgut, the dorsal and ventral pancreatic buds, and beta-cells in the Islets of Langerhans all notably express HB9. HB9 deficient mice fail to develop a dorsal pancreatic lobe. Placing HB9 proximally in the transcriptional factor hierarchy that controls pancreas development, the dorsal epithelium of the HB9 -/- mice never adopts a pancreatic phenotype. Furthermore, the remnant HB9 -/- pancreases have small islets of Langerhans with reduced numbers of insulin producing cells. Thus, HB9 is key for normal pancreas development and function. - B-lymphocyte, transcription, pancreas, motor neuron, development, apoptosis.
| Thaler, J; Harrison, K; Sharma, K et al. (1999) Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron 23:675-87 |
| Harrison, K A; Thaler, J; Pfaff, S L et al. (1999) Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet 23:71-5 |
