Transcription factor KLF7 is important for neuronal morphogenesis in selected regions of the nervous system.
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 p21waf/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 p21waf/cip and p27kip1 genes. Cotransfection experiments extended the last finding by documenting KLF7's ability to transactivate a reporter gene construct driven by the proximal promoter of p27kip1. Consistent with emerging evidence for a role of Cip/Kip proteins in cytoskeletal dynamics, we also documented p21waf/cip and p27kip1 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.
Laub
Friedrich
F
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 St., New York, New York 10021, USA.
Lei
Lei
L
Sumiyoshi
Hideaki
H
Kajimura
Daisuke
D
Dragomir
Cecilia
C
Smaldone
Silvia
S
Puche
Adam C
AC
Petros
Timothy J
TJ
Mason
Carol
C
Parada
Luis F
LF
Ramirez
Francesco
F
D000818:Animals; D001369:Axons / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology* / Q000254:growth & development; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D020964:Embryo Loss / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009831:Olfactory Mucosa / Q000166:cytology; D011401:Promoter Regions, Genetic; D012160:Retina / Q000166:cytology; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C426008:Klf7 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors