Transcription Factor KLF7 Is Important for Neuronal Morphogenesis in Selected Regions of the Nervous System

Abstract

The Krüppel-like transcription factors (KLFs) are important regulators of cell proliferation and differentiation in several different organ systems. The mouse Klf7 gene is strongly active in postmitotic neuroblasts of the developing nervous system, and the corresponding protein stimulates transcription of the cyclin-dependent kinase inhibitor p21^waf/cip gene. Here we report that loss of KLF7 activity in mice leads to neonatal lethality and a complex phenotype which is associated with deficits in neurite outgrowth and axonal misprojection at selected anatomical locations of the nervous system. Affected axon pathways include those of the olfactory and visual systems, the cerebral cortex, and the hippocampus. In situ hybridizations and immunoblots correlated loss of KLF7 activity in the olfactory epithelium with significant downregulation of the p21^waf/cip and p27^kip1 genes. Cotransfection experiments extended the last finding by documenting KLF7's ability to transactivate a reporter gene construct driven by the proximal promoter of p27^kip1. Consistent with emerging evidence for a role of Cip/Kip proteins in cytoskeletal dynamics, we also documented p21^waf/cip and p27^kip1 accumulation in the cytoplasm of differentiating olfactory sensory neurons. KLF7 activity might therefore control neuronal morphogenesis in part by optimizing the levels of molecules that promote axon outgrowth.

ACKNOWLEDGMENTS

We thank F. Margolis, P. Mombaerts, G. Sonenshein, T. Curran, and B. Vogelstein for providing critical reagents; T. Sakurai for invaluable comments on the manuscript; S. Lee-Arteaga and C. Else for excellent technical assistance; and K. Johnson for preparing the manuscript.

This work was supported by NIH grants NS33199 (L. F. Parada) and AR38648, the New York State Spinal Cord Injury Research Program, the St. Giles Foundation, and the James D. Farley family.