Generation of mice with a conditional allele for the p75<sup>NTR</sup> neurotrophin receptor gene

Bogenmann, Emil; Thomas, Penny S.; Li, Qianfeng; Kim, Jieun; Yang, Liang-Tung; Pierchala, Brian A.; Kaartinen, Vesa

doi:10.1002/dvg.20747

Cited by 47 publications

(64 citation statements)

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“…To investigate how adipose tissue contributes to the lean phenotype and insulin sensitivity of p75 NTR−/− mice on a HFD, we knocked out p75NTR specifically in adipocytes ( p75 AKO ) using conditional p75 NTR knockout ( p75 F/F ) (Bogenmann et al, 2011) and aP2-cre ( Adipocyte-cre ) mice that show gene recombination specifically in adipocytes without gene recombination in brain, muscle, liver, stromal vascular cells, and macrophages (Ahmadian et al, 2011; Barak et al, 2002; He et al, 2003; Lee et al, 2014; Li et al, 2011; Paschos et al, 2012; Qi et al, 2009). In p75 AKO mice, p75 NTR was specifically deleted in adipose tissue and not the brain and muscle (Figures 5A and 5B).…”

Section: Resultsmentioning

confidence: 99%

“…Heterozygous p75 NTR+/− mice were crossed to obtain p75 NTR−/− , p75 NTR+/− and p75 NTR+/+ littermates. p75 NTRflox/flox ( p75 F/F ) (Bogenmann et al, 2011) mice in the C57BL/6J background were also used. Crossings between p75 F/F and Adipocyte-cre , or MCK-cre were performed to generate p75 AKO ( AP2-cre∷p75 NTRflox/flox ) or p75 MKO ( MCK-cre∷p75 NTRflox/flox ) mice.…”

Section: Methodsmentioning

confidence: 99%

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p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

Baeza-Raja

Sachs

et al. 2016

Cell Reports

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Summary Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here we show that upon high-fat diet (HFD), the p75 neurotrophin receptor (p75NTR) controls energy expenditure in obese mice. Despite no changes in food intake, p75NTR-null mice were protected from HFD-induced obesity and remained lean due to increased energy expenditure, without developing insulin resistance or liver steatosis. p75NTR directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75NTR or transplantation of p75NTR-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75NTR to cAMP/PKA regulates energy balance and suggest that non-neuronal functions of neurotrophin receptor signaling could be a new target for treating obesity and the metabolic syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

Baeza-Raja

Sachs

et al. 2016

Cell Reports

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“…Different deletion mutants of p75 NTR exhibit complex sensory and sympathetic abnormalities that vary depending on the precise mutation (Davies, Lee, & Jaenisch, 1993; Dhanoa, Krol, Jahed, Crutcher, & Kawaja, 2006; Lee et al, 1992; Majdan, Walsh, Aloyz, & Miller, 2001; Petrie et al, 2013; von Schack et al, 2001). Conditional NCC-specific p75 NTR mutants show effects consistent with a disruption in PNS development (Bogenmann et al, 2011). Many of these studies have focused upon the role of p75 NTR in neuronal survival and innervation.…”

Section: Neurotrophic Factors In Sensory Neuron Developmentmentioning

confidence: 99%

Molecular Control of the Neural Crest and Peripheral Nervous System Development

Newbern

2015

Current Topics in Developmental Biology

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A transient and unique population of multipotent stem cells, known as neural crest cells (NCCs), generate a bewildering array of cell types during vertebrate development. An attractive model among developmental biologists, the study of NCC biology has provided a wealth of knowledge regarding the cellular and molecular mechanisms important for embryogenesis. Studies in numerous species have defined how distinct phases of NCC specification, proliferation, migration, and survival contribute to the formation of multiple functionally distinct organ systems. NCC contributions to the peripheral nervous system (PNS) are well known. Critical developmental processes have been defined that provide outstanding models for understanding how extracellular stimuli, cell–cell interactions, and transcriptional networks cooperate to direct cellular diversification and PNS morphogenesis. Dissecting the complex extracellular and intracellular mechanisms that mediate the formation of the PNS from NCCs may have important therapeutic implications for neurocristopathies, neuropathies, and certain forms of cancer.

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“…3B). p75 NTR plays an important role in the development of the PNS (11,19), and it is strongly expressed in the sciatic nerve (22). Therefore, we analyzed electron microscopy cross-sections of sciatic nerves from WT and p73KO mice.…”

Section: Tap73 Knockout Mice Show Defects In Heat Sensitivity With Dementioning

confidence: 99%

TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor

Niklison-Chirou

Steinert

Agostini

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Total and N-terminal isoform selective p73 knockout mice show a variety of central nervous system defects. Here we show that TAp73 is a transcriptional activator of p75 neurotrophin receptor (p75 NTR ) and that p75 NTR mRNA and protein levels are strongly reduced in the central and peripheral nervous systems of p73 knockout mice. In parallel, primary cortical neurons from p73 knockout mice showed a reduction in neurite outgrowth and in nerve growth factor-mediated neuronal differentiation, together with reduced miniature excitatory postsynaptic current frequencies and behavioral defects. p73 null mice also have impairments in the peripheral nervous system with reduced thermal sensitivity, axon number, and myelin thickness. At least some of these morphological and functional impairments in p73 null cells can be rescued by p75 NTR re-expression. Together, these data demonstrate that loss of p75 NTR contributes to the neurological phenotype of p73 knockout mice.73 is a transcription factor belonging to the p53 family, whose members share similarities in sequence and function (1-4). p73 can be transcribed from two different promoters: transcription from the upstream P1 promoter generates TAp73 isoforms containing a transactivation (TA) domain, and transcription from the P2 promoter generates truncated proteins that lack the TA domain and are known as ΔNp73. The C-terminal region of p73 is expressed, at least at the mRNA level, as a number of alternatively spliced TAp73 and ΔNp73 C-terminal isoforms (α, β, γ, ζ, δ, e, η), although it remains unclear whether all of these are also represented at the protein level (5, 6).The p75 neurotrophin receptor (p75 NTR ) is a member of the death receptor family, which can also be expressed in a variety of isoforms and functions as a low-affinity receptor for neurotrophins (7,8). It is abundantly expressed on neurons and glia in the developing nervous system (as well as on some other cell types such as B lymphocytes and natural killer cells), although it is much less abundant in adult brain. The effects of ligand binding to p75 NTR depend on p75 NTR 's interaction with other coreceptors. Thus, interaction with tropomyosin-related kinase A (TrkA) results in high-affinity binding of neurotrophins such as nerve growth factor (NGF) and cell survival. In contrast, neurotrophin interaction with the p75 NTR /sortilin complex leads to apoptosis, whereas p75 NTR can also form part of the Nogo receptor complex, which is activated by myelin proteins to inhibit axonal growth (9). Deletion of p75 NTR results in a profound loss of sensory but not motor neurons in dorsal root ganglia, with an increase in basal forebrain cholinergic neurons, confirming that p75 NTR can mediate both survival and apoptotic effects. The defect in sensory innervation arises because the peripheral axons are stunted and show reduced arborization (10, 11). In the central nervous system, p75 NTR -deficient mice also show significantly reduced hippocampal neurogenesis, with a smaller granular cell layer and dentate gyrus,...

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Generation of mice with a conditional allele for the p75^NTR neurotrophin receptor gene

Cited by 47 publications

References 50 publications

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

Molecular Control of the Neural Crest and Peripheral Nervous System Development

TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor

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Generation of mice with a conditional allele for the p75NTR neurotrophin receptor gene

Cited by 47 publications

References 50 publications

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity

Molecular Control of the Neural Crest and Peripheral Nervous System Development

TAp73 knockout mice show morphological and functional nervous system defects associated with loss of p75 neurotrophin receptor

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Generation of mice with a conditional allele for the p75^NTR neurotrophin receptor gene