Thyroid-specific enhancer-binding protein (T/EBP) is a homeodomain- containing DNA-binding protein which controls expression of thyroid- and lung-specific genes such as those encoding thyroid peroxidase, thyroglobulin, thyroid stimulating hormone (TSH) receptor and the Na+/I- symporter , and surfactant proteins A, B, and C, and clara cell secretory protein, respectively. A role for T/EBP in mammalian development has been suggested after T/EBP was found to be expressed in rat embryos. Our earlier work on targeted disruption of the mouse T/ebp gene has conclusively demonstrated that T/EBP is essential for organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Our current work is focused on understanding the role of T/EBP during development, especially in the lung and brain. To this end, analyses of these organs in T/ebp-null mouse have been carried out by using histopathological analyses, in situ hybridization, and immunohistochemistry.T/ebp-null mouse embryos die at birth due to respiratory insufficiency caused by profoundly abnormal lungs that do not seem to undergo branching morphogenesis beyond the formation of the mainstem bronchi and therefore consist solely of dilated tracheobronchial structures. The mutant embryo lungs were examined for the spatial and temporal expression pattern of a number of extracellular matrix proteins and their cellular receptors, including alpha-integrins, laminin and collagen type IV, and differentially spliced vascular endothelial growth factor transcripts. The data suggested that at least two separate pathways may exist in embryonic lung morphogenesis: proximal lung morphogenesis that is T/ebp independent and distal lung morphogenesis that appears to be strictly dependent on the wild type activity of T/ebp.T/ebp is expressed in the anlage of the pallidum, the ventral region of the basal ganglia within the telencephalon in the brain during early embryogenesis. Detailed analyses of the telencephalon in the mutant embryos revealed that a mouse deficient in T/ebp function does not form pallidal structures, lacks basal forebrain cholinergic neurons and has reduced numbers of cortical cells expressing GABA, DLX2 and calbindin that migrate from the pallidum through the striatum and into the cortex. These phenotypes appear to result from a ventral-to-dorsal transformation of the pallidal primordium into a striatal-like anlage, suggesting that T/ebp is required both for regional specification of the ventral telencephalon and for the production of specific cell types that migrate into the striatum and cerebral cortex. - Animal models, Development, DNA binding protein, Transcription Factor, Gene Targeting, Homeobox Gene, lung, brain, Organogenesis, - Neither Human Subjects nor Human Tissues
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