title: Cux2 acts as a critical regulator for neurogenesis in the olfactory epithelium of vertebrates.
abstract: Signaling pathways and transcription factors are crucial regulators of vertebrate neurogenesis, exerting their function in a spatial and temporal manner. Despite recent advances in our understanding of the molecular regulation of embryonic neurogenesis, little is known regarding how different signaling pathways interact to tightly regulate this process during the development of neuroepithelia. To address this, we have investigated the events lying upstream and downstream of a key neurogenic factor, the Cut-like homeodomain transcription factor-2 (Cux2), during embryonic neurogenesis in chick and mouse. By using the olfactory epithelium as a model for neurogenesis we have analyzed mouse embryos deficient in Cux2, as well as chick embryos exposed to Cux2 silencing (si) RNA or a Cux2 over-expression construct. We provide evidence that enhanced BMP activity increases Cux2 expression and suppresses olfactory neurogenesis in the chick olfactory epithelium. In addition, our results show that up-regulation of Cux2, either BMP-induced or ectopically over-expressed, reduce Delta1 expression and suppress proliferation. Interestingly, the loss of Cux2 activity, using mutant mice or siRNA in chick, also diminishes neurogenesis, Notch activity and cell proliferation in the olfactory epithelium. Our results suggest that controlled low levels of Cux2 activity are necessary for proper Notch signaling, maintenance of the proliferative pool and ongoing neurogenesis in the olfactory epithelium. Thus, we demonstrate a novel conserved mechanism in vertebrates in which levels of Cux2 activity play an important role for ongoing neurogenesis in the olfactory epithelium.
authors: Umeå Centre for Molecular Medicine, Umeå University, Building 6M 4th floor, 901 87 Umeå, Sweden. Electronic address: walter.wittmann@umu.se.
authors: Walter
authors: W
authors: Wittmann
authors: Department of Medical Neuroscience, Dalhousie University, Halifax, Canada. Electronic address: angelo.iulianella@dal.ca.
authors: Angelo
authors: A
authors: Iulianella
authors: Umeå Centre for Molecular Medicine, Umeå University, Building 6M 4th floor, 901 87 Umeå, Sweden. Electronic address: lena.gunhaga@umu.se.
authors: Lena
authors: L
authors: Gunhaga
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009831:Olfactory Mucosa / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C101672:Cux2 protein, mouse; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D051880:Receptors, Notch
keywords: BMP; Chick; Cux2; Development; Mouse; Neurogenesis; Notch; Olfactory