The Notch pathway is prominent among those known to regulate neural development in vertebrates. Notch receptor activation can inhibit neurogenesis, maintain neural progenitor character, and in some contexts promote gliogenesis and drive binary fate choices. Recently, a wave of exciting studies has emerged, which has both solidified previously held assertions and expanded our understanding of Notch function during neurogenesis and in the adult brain. These studies have examined pathway regulators and interactions, as well as pathway dynamics, with respect to both gene expression and cell-cell signaling. Here, focusing primarily on vertebrates, we review the current literature on Notch signaling in the nervous system, and highlight numerous recent studies that have generated interesting and unexpected advances.

SUMMARY Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. This work shows that Notch signaling is dynamically regulated in response to neuronal activity, that Arc/Arg3.1 is a novel context-dependent Notch regulator, and that Notch1 is required for the synaptic plasticity that contributes to memory formation.

The neuropathological hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, presumably mediated by apoptosis. The homeobox transcription factors engrailed 1 and engrailed 2 are expressed by this neuronal population from early in development to adulthood. Despite a large mid-hindbrain deletion in double mutants null for both genes, mesencephalic dopaminergic (mDA) neurons are induced, become postmitotic and acquire their neurotransmitter phenotype. However, at birth, no mDA neurons are left. We show that the entire population of these neurons is lost by E14 in the mutant animals, earlier than in any other described genetic model system for Parkinson’s disease. This disappearance is caused by apoptosis revealed by the presence of activated caspase 3 in the dying tyrosine hydroxylase-positive mutant cells. Furthermore, using in vitro cell mixing experiments and RNA interference on primary cell culture of ventral midbrain we were able to show that the demise of mDA neurons in the mutant mice is due to a cell-autonomously requirement of the engrailed genes and not a result of the missing mid-hindbrain tissue. Gene silencing in the postmitotic neurons by RNA interference activates caspase 3 and induces apoptosis in less than 24 hours. This rapid induction of cell death in mDA neurons suggests that the engrailed genes participate directly in the regulation of apoptosis, a proposed mechanism for Parkinson’s disease.

The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1؊͞؊; En2؊͞؊). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1؉͞؊;En2؊͞؊), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.dopamine ͉ midbrain ͉ mouse mutant ͉ neurodegenerative disease ͉ substantia nigra M esencephalic dopaminergic (mesDA) neurons are the main source of dopamine in the mammalian central nervous system (1). They are located in three distinct nuclei, the substantia nigra pars compacta (SN), the ventral tegmentum (VTA), and the retrorubral field (RRF). Their main innervation targets are the basal ganglia, where they play a major role in controlling emotion, motivation, and motor behavior (2, 3), recognized by their involvement in schizophrenia, addiction, and most prominently in Parkinson's disease (PD; ref. 4). PD is a multisystemic degenerative disorder of the central and peripheral nervous systems. Its hallmark is the progressive degeneration of DA neurons in the SN. The clinical symptoms are resting tremor; muscular rigidity; postural instability; hyposomia; a positive response to the application of L-3,4-dihydroxyphenylalanine (L-DOPA); and the presence of cytoplasmatic inclusions (Lewy bodies) in postmortem brains (5). Additionally, PD patients are often characterized by weight loss starting before diagnosis and continuing with disease progression (6, 7).The homeodomain transcription factors Engrailed-1 and -2 (En1 and En2) are expressed by all mesDA neurons soon after differentiation and then continuously into adulthood. They are cell-autonomously and in a gene-dose-dependent manner required for the survival of this neuronal population, leading to the complete loss of the cells in mutant mice homozygous null for both genes (En1Ϫ͞Ϫ;En2Ϫ͞Ϫ; refs. 8 and 9). In their function as survival factors for mesDA neurons, the two genes are redundant and can compensate for each other (9, 10). The single-null mutants for either En1 (En1Ϫ͞Ϫ) or En2 (En2Ϫ͞Ϫ) show no significant alterations in the organization of the mesDA system at birth, but the mice with genotypes intermediate to the single and double mutants are distinctively different from each other. Whereas En1Ϫ͞Ϫ;En2ϩ͞Ϫ mice die at po...

As for any other cell population, the development, cell fate, and properties of mesencephalic dopaminergic (mesDA) neurons are ultimately controlled at the transcriptional level. The genes for two transcription factors Engrailed-1 ( En1) and Engrailed-2 ( En2) play an essential role in the development and maintenance of these cells. They belong to a family of genes that have been investigated in Drosophila for more than half a century. The products of these genes are all characterized by homeotic tissue transformation and a highly conserved protein sequence, the homeobox. En1 and En2 act upon at least two steps of the differentiation of mesDA neurons. They take part in the regionalization event, which gives rise to the neuroepithelium that provides the precursor cells in the ventral midbrain with the fibroblast growth factor 8 signal necessary for their induction. Additionally, these genes are required in postmitotic mesDA neurons in which they are expressed from embryonic day 12 continuously into adulthood. In mutant mice homozygous null for En1 and En2, the neurons are generated in the ventral midbrain, become postmitotic, and begin to express their neurotransmitter phenotype. However, thereafter, they rapidly die by apoptosis. Cell mixing experiments in vitro and in vivo have demonstrated that the engrailed requirement for the survival of mesDA neurons is cell-autonomous. The inactivation of engrailed by RNA interference induces apoptosis in less than 24 h. These data suggest that the engrailed genes control an essential mechanism for the survival of mesDA neurons.

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The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer.

A down-modulation of both the 55-kDa (TNF-R55) and the 75-kDa (TNF-R75) TNF receptors is observed in neutrophils exposed to a variety of stimuli. Proteolytic cleavage of the extracellular region of both receptors (shedding) and, with TNF, internalization of TNF-R55 and shedding of TNF-R75 are the proposed mechanisms. We have characterized the TNF-induced shedding of TNF receptors in neutrophils and determined the nature of the involved proteinase. Neutrophils exposed to TNF release both TNF receptors. A release of TNF receptors comparable to that observed with TNF was induced with TNF-R55-specific reagents (mAbs and a mutant of TNF) but not with the corresponding TNF-R75-specific reagents. A hydroxamic acid compound (KB8301) almost completely inhibited shedding of TNF-R55 and to a lesser degree shedding of TNF-R75. KB8301 also inhibited FMLP-induced shedding to a similar extent. Shedding was also inhibited by 1,10-phenanthroline, but this effect was considered nonspecific as the compound, at variance with KB8301, almost completely inhibited TNF and FMLP-induced PMN activation. Diisopropylfluorophosphate partially inhibited shedding of TNF-R75, suggesting the contribution of a serine proteinase to the release of this receptor. Shedding activity was not affected by matrix metalloproteinases inhibitors nor was it released in the supernatants of FMLP-stimulated neutrophils. These results suggest that TNF induces release of its receptors, that such a release is mediated via TNF-R55, and that a membrane-bound and non-matrix metalloproteinase is involved in the process. The possibility that ADAM-17, which we show to be expressed in neutrophils, might be the involved proteinase is discussed.