contributed equally to this work Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity. Keywords: brain-derived neurotrophic factor (BDNF)/ hypothalamus/neurotrophins/obesity/TrkB IntroductionIn the last decade, many genes responsible for the signals underlying eating behavior and obesity have been identified. These factors include well described peripheral mediators such as insulin, glucocorticoids and leptin, as well as central mediators that are less well understood (Rosenbaum et al., 1997). The current animal models of obesity focus upon the hypothalamus as the anatomical area within the brain that controls eating behavior. In the 1940s, it was shown that hypothalamic lesions cause hyperphagia and obesity (Hetherington and Ranson, 1942). Today, several genetic models give further insight into the hypothalamus and weight regulation. In the ob and db mouse models, either leptin (ob) or its hypothalamic receptor (db) are mutated and rendered non-functional, resulting in severe early-onset obesity (Coleman, 1978;Caro et al., 1996;Chen et al., 1996;Lee et al., 1996). Overexpression of the agouti peptide or gene-targeted deletion of the hypothalamic receptor it antagonizes, the melanocortin-4 receptor, also result in obesity (Lu et al., 1994;Huszar et al., 1997). Each of these models demonstrates the importance of various specific nuclei within 1290 © European Molecular Biology Organization the hypothalamus including the arcuate, dorsomedial, ventromedial and paraventricular nuclei (Chua et al., 1996;Fan et al., 1997). Additionally, at least two new families of peptides, the orexins and cocaine-and amphetaminerelated transcript (CART), have been localized to the hypothalamus. These factors are thought to mediate feeding behavior in response to neural cues that act upon the satiety centers of the hypothalamus (Kristensen et al., 1998;Sakurai et al., 1998).The neurotrophin (NTF) family is composed of four structurally related proteins with similar functions in promoting neuronal survival within the peripheral nervous system (PNS) (Barde, 1994;Snider, 1998). NTF-deficient mice have been particularly useful in studying nervous system development, as nerve growth factor (NGF), brainderived neurotroph...

It is becoming increasingly clear that brain injuries from a variety of causes stimulate neurogenesis within the hippocampus. It remains unclear, however, how robust this response may be and what primary cell types are involved. Here, using a controlled cortical impact model of traumatic brain injury on a previously characterized transgenic mouse line that expresses enhanced green fluorescent protein (eGFP) under the control of the nestin promoter, we demonstrate that it is the earliest type-1 quiescent progenitor cells that are induced to proliferate and migrate outside the subgranular layer of the dentate gyrus. This type-1 cell activation occurs at the same time that we observe adjacent but more differentiated doublecortin-expressing progenitors (type-2 cells) being eliminated. Also, although type-2 cells remain intact in the contralateral (uninjured) dentate gyrus, the type-1 cells there are also activated and result in increased numbers of the doublecortin-expressing type-2 cells. In addition, we have generated a novel mouse transgenic that expresses a modified version of the herpes simplex virus thymidine kinase along with eGFP that allows for the visualization and inducible ablation of early dividing progenitors by exposing them to ganciclovir. Using this transgenic in the context of traumatic brain injury, we demonstrate that these early progenitors are required for injury-induced remodeling to occur. This work suggests that injury-induced hippocampal remodeling following brain injury likely requires sustained activation of quiescent early progenitors.

Gene-targeting experiments of Trk receptors and neurotrophins has confirmed the expectation that embryonic sensory and sympathetic neurons require neurotrophin function for survival. They have further revealed correlation between a specific neurotrophin requirement and eventual sensory modality. We have analyzed embryonic and neonatal mice with mutations in the BDNF, neurotrophin 3 (NT-3), and TrkC genes. Our data confirm an unexpectedly high proportion of sensory neuron losses in NT-3 (>70%), BDNF (>20%), and TrkC (>30%) mutants, which encompass populations thought to be NGF-dependent. Direct comparison of TrkC and NT-3 mutants indicates that only a subset of the NT-3-dependent neurons also requires TrkC. The observed losses in our TrkC mutant, which is null for all proteins encoded by the gene, are more severe than those previously reported for the kinase-negative TrkC mutation, implicating additional and important functions for the truncated receptors. Our data further indicate that mature NGF-requiring neurons undergo precocious and transitory requirements for NT-3 and/or BDNF. We suggest that neurotrophins may function in creating early heterogeneity that would enable ganglia to compensate for diverse modality requirements before the period of naturally occurring death.

The NF-jB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-jB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-a-and LPSmediated NF-jB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-jB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-jB and JNK activation in response to TNF-a, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-a-, IL-1-and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-jB activation. Thus, TAX1BP1 is pivotal for the termination of NF-jB and JNK signaling by functioning as an essential regulator of A20.

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