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Molecular and Cellular Biology, July 2005, p. 5699-5711, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5699-5711.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Friedrich Laub,^1,2 Lei Lei,³ Hideaki Sumiyoshi,^1, Daisuke Kajimura,¹ Cecilia Dragomir,¹ Silvia Smaldone,^1,2 Adam C. Puche,⁴ Timothy J. Petros,⁵ Carol Mason,^5,6 Luis F. Parada,³ and Francesco Ramirez^1,2*

Laboratory of Genetics and Organogenesis, Research Division of the Hospital for Special Surgery, and Department of Physiology and Biophysics at Weill Medical College of Cornell University, 535 East 70th Street, New York, New York 10021,¹ CEINGE-Biotecnologie Avanzate, 80131 Naples, Italy,² Center for Developmental Biology and Kent Waldrep Center for Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390-9133,³ Department of Anatomy and Neurobiology, School of Medicine, University of Maryland, 20 Penn St., Baltimore, Maryland 21201,⁴ Center for Neurobiology and Behavior,⁵ Department of Pathology, Columbia University, 630 West 168th Street, New York, New York 10032⁶

Received 30 December 2004/ Returned for modification 12 March 2005/ Accepted 7 April 2005

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.

Present address: Department of Anatomy, Biology and Medicine, Oita Medical University, Oita 879-5593, Japan.

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