Abstract
The transforming growth factor betas (TGFβs) are context-dependent regulators of neurons in vitro, but their physiological functions in the brain are unclear. Haploinsufficiency of either Tgfβ1 or Tgfβ2 leads to age-related deterioration of neurons, but the development of the brain is normal in the full absence of either of these genes. However, some individuals with mis-sense mutations of TGFβ receptors are mentally retarded, suggesting that the TGFβ isoforms can compensate for each other during brain development. This possibility was tested by generating mice (NSE × PTR) with neuron-specific expression of a dominant-negative inhibitor of TGFβ signaling. The NSE × PTR mice with a FVBxC57Bl/6 genetic background were viable and developed normally despite strong neuronal expression of the inhibitor of TGFβ signaling. Their cerebella were of normal size and contained normal numbers of neurons. When the genetic background of the mice was changed to C57BL/6, the phenotype of the mice became neonatal lethal, with the neonates exhibiting various malformations. The malformations correlated with sites of non-neuronal expression of the transgenes and included facial dysmorphogenesis, incomplete closure of the ventral body wall and absence of intestinal motility. The C57BL/6 Tgfbm1–3 alleles, which modulate the phenotype of Tgfβ1−/− mice, were not major determinants of the NSE × PTR phenotype. The data suggest that the development of the cerebellum is insensitive to the level of TGFβ signaling, although this may be dependent on the genetic background.
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Acknowledgments
We thank Mrs. Nichola Batchelor for her expert care of the murine colonies and Mrs. Janet McLay for her technical support. The support of the Marsden Fund (Royal Society of New Zealand) is acknowledged, with our appreciation.
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Asano, Y., Koishi, K., Frugier, T. et al. Mice with Disrupted TGFβ Signaling Have Normal Cerebella Development, but Exhibit Facial Dysmorphogenesis and Strain-Dependent Deficits in Their Body Wall. Cell Mol Neurobiol 29, 621–633 (2009). https://doi.org/10.1007/s10571-009-9354-x
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DOI: https://doi.org/10.1007/s10571-009-9354-x