Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells.

Vascular endothelial growth factor (VEGF) intracellular signaling in endothelial cells is initiated by the activation of distinct tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1/KDR). Because the tyrosine kinase-dependent transcription factors known as STAT (signal transducers and activators of transcription) proteins are important modulators of cell growth responses induced by other growth factor receptors, we have determined the effects VEGF of on STAT activation in BAEC (bovine aortic endothelial cells). Here, we show that VEGF induces tyrosine phosphorylation and nuclear translocation of STAT1 and STAT6. VEGF also stimulates STAT3 tyrosine phosphorylation, but nuclear translocation does not occur. We found that placenta growth factor, which selectively activates VEGFR1, has no effect on the STATs. However, upon VEGF stimulation, STAT1 associates with the VEGFR2 in a tyrosine kinase-dependent manner, indicating that VEGF-induced STAT1 activation is mediated primarily by VEGFR2. Thus, our study shows for the first time that VEGF activates the STAT pathway through VEGFR2. Because the growth-promoting activity of VEGF depends upon VEGFR2 activation, these findings suggest a role for the STATs in the regulation of gene expression associated with the angiogenic effects of VEGF.

DiI labeling and homeobox gene islet-1 expression reveal the contribution of ventral neural tube cells to the formation of the avian trigeminal ganglion.

Cells of the neural tube are thought to be committed to form only the central nervous system, whereas the peripheral nervous system is believed to be derived from neural crest cells and from placodes, which are specialized regions of the surface ectoderm. Neural crest cells arise early from the dorsal part of the neural tube. The possibility that after emigration of the neural crest cells, another population of cells arising from the ventral part of the neural tube also emigrates via a different route was examined. Here we report that, after labeling cells of the ventral neural tube in the rostral hindbrain of E3 duck embryos with DiI, they were later found in the trigeminal ganglion of the fifth cranial nerve. A trail of labeled cells could be traced from the ventral part of the neural tube to the peripheral ganglion. Further, expression of the homeobox gene Islet-1 in cells of the neural tube and the ganglion also indicated that some ventral neural tube cells may normally emigrate to the trigeminal ganglion. It is concluded that not all neural tube cells are committed to form the central nervous system; the ventral part of the neural tube also provides cells for the formation of the trigeminal ganglion. These results raise the possibility that the ventral neural tube may serve as an additional source of cells for the formation of various other components of the peripheral nervous system.

Dependence of cranial motor neuron formation on ventromedial brain stem.

The formation of motor neurons in the spinal cord is dependent on inductive signals from the floor plate and notochord. Motor neurons in the brain stem, on the other hand, develop in the absence of both structures. This suggests that either the germinal epithelium is specified intrinsically to form specific cranial motor nuclei or that the inductive signals for the formation of cranial motor neurons arise from some other structure. These possibilities were investigated experimentally by using the formation of trochlear motor neurons in the midbrain of duck embryos as a model system. The trochlear motor neurons, which form the nucleus of the fourth cranial nerve, developed normally after early damage to the prospective germinal epithelium, suggesting that it is unlikely to be specified intrinsically to form these cranial motor neurons. Instead, their development was found to be dependent on the cells within, or associated with, the ventromedial region of the brain stem, as the extirpation of this region results in the absence of motor neuron formation. These results show that structures other than the floor plate and notochord provide inductive signals for the cellular differentiation and patterning of the developing central nervous system. The raise the possibility that the inductive signals for motor neuron differentiation in the spinal cord and the brain stem may not be necessarily identical.

Formation of the cranial motor neurons in the absence of the floor plate.

The inductive signals for the differentiation of motor neurons in the spinal cord have been experimentally shown to arise from cells in the midventral region of the neural tube, often referred to as the floor plate, and from the notochord. Although the prevailing view is that a similar mechanism accounts for the differentiation of motor neurons in the brain stem, supporting experimental evidence is lacking. Here, using the formation of the trochlear nucleus in the midbrain of duck embryos as a model system, we report that the floor plate and the notochord are not necessary for the development of these motor neurons in the brain stem. Early damage to the floor plate or extirpation of the floor plate and notochord does not prevent the development of these cranial motor neurons. Thus, either the inductive signals for the formation of these cranial motor neurons arise from some other structure or the germinal epithelium of the cranial neural tube is intrinsically programmed to form specific cranial motor nuclei.