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Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling.

ABSTRACT: Neurotrophins regulate diverse aspects of neuronal development and plasticity, but their precise in vivo functions during neural circuit assembly in the central brain remain unclear. We show that the neurotrophin receptor tropomyosin-related kinase C (TrkC) is required for dendritic growth and branching of mouse cerebellar Purkinje cells. Sparse TrkC knockout reduced dendrite complexity, but global Purkinje cell knockout had no effect. Removal of the TrkC ligand neurotrophin-3 (NT-3) from cerebellar granule cells, which provide major afferent input to developing Purkinje cell dendrites, rescued the dendrite defects caused by sparse TrkC disruption in Purkinje cells. Our data demonstrate that NT-3 from presynaptic neurons (granule cells) is required for TrkC-dependent competitive dendrite morphogenesis in postsynaptic neurons (Purkinje cells)--a previously unknown mechanism of neural circuit development.

SUBMITTER: Joo W

PROVIDER: S-EPMC4631524 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling.

Joo William W Hippenmeyer Simon S Luo Liqun L

Science (New York, N.Y.) 20141001 6209

Neurotrophins regulate diverse aspects of neuronal development and plasticity, but their precise in vivo functions during neural circuit assembly in the central brain remain unclear. We show that the neurotrophin receptor tropomyosin-related kinase C (TrkC) is required for dendritic growth and branching of mouse cerebellar Purkinje cells. Sparse TrkC knockout reduced dendrite complexity, but global Purkinje cell knockout had no effect. Removal of the TrkC ligand neurotrophin-3 (NT-3) from cerebe ...[more]

PMID: 25359972

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Project description:Neurons are highly polarized specialized cells. Neuronal integrity and functional roles are critically dependent on dendritic architecture and synaptic structure, function and plasticity. The cadherins are glycosylated transmembrane proteins that form cell adhesion complexes in various tissues. They are associated with a group of cytosolic proteins, the catenins. While the functional roles of the complex have been extensively investigates in non-neuronal cells, it is becoming increasingly clear that components of the complex have critical roles in regulating dendritic and synaptic architecture, function and plasticity in neurons. Consistent with these functional roles, aberrations in components of the complex have been implicated in a variety of neurodevelopmental disorders. In this review, we discuss the roles of the classical cadherins and catenins in various aspects of dendrite and synapse architecture and function and their relevance to human neurological disorders. Cadherins are glycosylated transmembrane proteins that were initially identified as Ca(2+)-dependent cell adhesion molecules. They are present on plasma membrane of a variety of cell types from primitive metazoans to humans. In the past several years, it has become clear that in addition to providing mechanical adhesion between cells, cadherins play integral roles in tissue morphogenesis and homeostasis. The cadherin family is composed of more than 100 members and classified into several subfamilies, including classical cadherins and protocadherins. Several of these cadherin family members have been implicated in various aspects of neuronal development and function. (1-3) The classical cadherins are associated with a group of cytosolic proteins, collectively called the catenins. While the functional roles of the cadherin-catenin cell adhesion complex have been extensively investigated in epithelial cells, it is now clear that components of the complex are well expressed in central neurons at different stages during development. (4,5) Recent exciting studies have shed some light on the functional roles of cadherins and catenins in central neurons. In this review, we will provide a brief overview of the cadherin superfamily, describe cadherin family members expressed in central neurons, cadherin-catenin complexes in central neurons and then focus on role of the cadherin-catenin complex in dendrite morphogenesis and synapse morphogenesis, function and plasticity. The final section is dedicated to discussion of the emerging list of neural disorders linked to cadherins and catenins. While the roles of cadherins and catenins have been examined in several different types of neurons, the focus of this review is their role in mammalian central neurons, particularly those of the cortex and hippocampus. Accompanying this review is a series of excellent reviews targeting the roles of cadherins and protocadherins in other aspects of neural development.

Project description:BackgroundTrkC, a member of neurotrophin receptor family, functions not only as an oncogene, but also act as a tumor suppressor via a manner of dependence receptor in human malignant tumors. Little is known on the action of TrkC for the clinical prognosis and the progression of breast cancer according to the availability of its ligand NT-3. We sought to investigate the prognostic relevance of NT-3-TrkC axis in breast cancer and estimate its role during the process of breast cancer progression.Methods236 cases of invasive ductal carcinoma (IDC), 60 pure ductal carcinoma in situ (DCIS) and 30 normal breast tissue (NBT) between 2004 and 2005 were included in the study. Spearman's rank correlation test was used to analyze the association of NT-3-TrkC expression and breast cancer progression. The Kaplan-Meier method and Cox proportional hazards model were performed to identify the relevant prognostic factors.Results50.4% IDC tumors displayed absent or low TrkC expression, while 49.6% was high TrkC expression. TrkC expression was negatively associated with lymph node metastasis (P = 0.029) and tumor proliferation (P = 0.015). Patients with lower TrkC expressing tumors had a higher risk of recurrence (odds ratio, 0.401; 95% confidence interval, 0.207-0.778; P = 0.007). The layered analysis indicated that patients with high TrkC expression tumors had a favor disease-free survival whether NT-3 and TrkC were co-expressed or solitarily expressed in the tumor (P = 0.000). NT-3 was demonstrated to be not a predictor of IDC patients' prognosis. But NT-3 expression was inversely correlated with the progression of breast cancer (r = -0.341, P = 0.000), since more IDC tumors showed high NT-3 expression than DCIS tumors (51.7% vs. 25.9%), while no NBT showed high NT-3 expression, as well.ConclusionThe study indicates TrkC expression reduces tumor relapse independent of NT-3 availability in the IDC. Elevated NT-3 expression contributes to the progression of breast cancer.

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Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling.

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Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling.

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