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The transcription factor Nurr1 is essential for the generation of midbrain dopaminergic neurons (mDA). Only a few Nurr1-regulated genes have so far been identified and it remains unclear how Nurr1 influences the development and function of dopaminergic neurons. To identify novel Nurr1 target genes we have used genome-wide expression profiling in rat midbrain primary cultures, enriched in dopaminergic neurons, following up-regulation of Nurr1 expression by depolarization. In this study we demonstrate that following depolarization the hyperexpression of Nurr1 and the brain derived neurotrophic factor (BDNF) are phospholipase C- and protein kinase C-dependent. We show that Bdnf, which encodes a neurotrophin involved also in the phenotypic maturation of mDA neurons, is a novel Nurr1 target gene. By RNA interference experiments we show that a decreased Nurr1 expression is followed by tyrosine hydroxylase and BDNF mRNA and protein down-regulation. Reporter gene assay experiments performed on midbrain primary cultures using four Bdnf promoter constructs show that Bdnf is a direct target gene of Nurr1. Taken together, our findings suggest that Nurr1 might also influence the development and the function of midbrain dopaminergic neurons via direct regulation of Bdnf expression. © 2007 The Authors.

Progranulin (GRN) gene mutations have been genetically associated with frontotemporal dementia (FTD) and are present in about 23% of patients with familial FTD. However, the neurobiology of this secreted glycoprotein remains unclear. Here, we report the identification of 3 pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We present evidence that all the available patients in these 3 familial cases are carrying the rare GRN gene exon 6 deletion g10325_10331delCTGCTGT (relative to nt 1 in NG_007886.1), alias Cys157LysfsX97. This mutation was previously described in 2 sporadic cases but was never associated with familial cases. Our patients demonstrate heterogeneous clinical phenotypes, such as the behavioral variant (bvFTD) in the affected men and the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) in the affected woman. Haploinsufficiency was revealed by both quantitative real-time PCR of the gene and protein analyses. These findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability.

Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer's disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-β protein precursor (AβPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-β peptides from AβPP is the primary event that subsequently induces abnormal tau phosphorylation. In this work, we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects, there is a stable pool of phospho-tau which remains strictly confined to neuronal nuclei, while nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AβPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons. © 2012 - IOS Press and the authors. All rights reserved.

Neural stem cell proliferation and differentiation play a crucial role in the formation and wiring of neuronal connections forming neuronal circuits. During neural tissues development, a large diversity of neuronal phenotypes is produced from neural precursor cells. In recent years, the cellular and molecular mechanisms by which specific types of neurons are generated have been explored with the aim to elucidate the complex events leading to the generation of different phenotypes via distinctive developmental programs that control self-renewal, differentiation, and plasticity. The extracellular environment is thought to provide instructive influences that actively induce the production of specific neuronal phenotypes. In this work, the secretome profiling of differentiated neural mes-c-myc A1 (A1) cell line endowed with stem cell properties was analyzed by applying a shotgun LC-MS/MS approach. The results provide a list of secreted molecules with potential relevance for the functional and biological features characterizing the A1 neuronal phenotype. Proteins involved in biological processes closely related to nervous system development including neurites growth, differentiation of neurons and axonogenesis were identified. Among them, proteins belonging to extracellular matrix and cell-adhesion complexes as well as soluble factors with well established neurotrophic properties were detected. The presented work provides the basis to clarify the complex extracellular protein networks implicated in neuronal differentiation and in the acquisition of the neuronal phenotype. This article is part of a Special Issue entitled: An Updated Secretome. © 2012 Elsevier B.V.

Kruppel-like factor 7 (KLF7) belongs to the large family of KLF transcription factors, which comprises at least 17 members. Within this family, KLF7 is unique since its expression is strictly restricted within the nervous system during development. We have previously shown that KLF7 is required for neuronal morphogenesis and axon guidance in selected regions of the nervous system, including hippocampus, olfactory bulbs and cortex, as well as in neuronal cell cultures. In the present work, we have furthered our analysis of the role of KLF7 in central nervous system development. By gene expression analysis during brain embryogenesis, we found significant alterations in dopaminergic neurons in Klf7 null mice. In particular, the tyrosine hydroxylase (TH) and dopamine transporter (Dat) transcripts are strongly decreased in the olfactory bulbs and ventral midbrain at birth, compared to wild-type littermates. Interestingly, Klf7-mutant mice show a dramatic reduction of TH-positive neurons in the olfactory bulbs, but no change in GABAergic or midbrain dopaminergic neurons. These observations raise the possibility that a lack of a KLF family member affects dopaminergic neuron development. (C) 2010 Elsevier Inc. All rights reserved.