Mice lacking NT-3, and its receptor TrkC, exhibit profound deficiencies in CNS glial cells

Kahn, M.A.; Kumar, Sumit; Liebl, Daniel J.; Chang, Ruth; Parada, Luis F.; Vellis, Jean de

doi:10.1002/(sici)1098-1136(199904)26:2<153::aid-glia6>3.0.co;2-z

Cited by 89 publications

(43 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reductions in both neuronal and glial cell populations have been observed in NT3 knockout mice. 49 Overexpression of trkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice. 44 TrkB knockout mice have decreased densities of axonal varicosities, lower densities of synaptic contacts, and decreased density of synaptic vesicles, 46 a finding that has been suggested in tubers and non-TSC cortical dysplasia.…”

Section: Altered Neurotrophin Expression and Aberrant Cytoarchitecturmentioning

confidence: 99%

“…For example, BDNF and NT3 promote the morphological differentiation of a subpopulation of GABAergic neurons in cortex 53 and a recent study showed markedly diminished numbers of GABAergic neurons in tubers as evidenced by GAD65 immunolabeling. 37 Similarly, NT3 and trkB have a role in the promotion of activity-dependent inhibitory synaptogenesis 48,49 and thus, reduced NT3 and trkB expression may alter the formation of inhibitory synapses in tubers. Reduced expression of several GABA A receptor subunits has been demonstrated in tubers and thus, a reduction in GABAergic neurons coupled with diminished GABA-mediated receptor inhibition may foster epileptogenesis.…”

Section: Neurotrophin Expression Epilepsy and Epileptogenesismentioning

confidence: 99%

See 1 more Smart Citation

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Kyin

Yang

Baybis

et al. 2001

The American Journal of Pathology

View full text Add to dashboard Cite

Neurotrophins and their receptors modulate cerebral cortical development. Tubers in the tuberous sclerosis complex (TSC) are characterized histologically by disorganized cortical cytoarchitecture and thus, we hypothesized that expression of neurotrophin mRNAs and proteins might be altered in tubers. Using in situ transcription and mRNA amplification to probe cDNA arrays, we found that neurotrophin-3 (NT3) and trkB mRNA expression were reduced whereas neurotrophin-4 (NT4) and trkC mRNA expression were increased in whole tuber sections. Alterations in mRNA abundance were defined in single microdissected dysplastic neurons (DNs) and giant cells (GCs). NT3 mRNA expression was reduced in GCs and trkB mRNA expression was reduced in DNs. NT4 mRNA expression was increased in DNs and trkC mRNA expression was increased in both DNs and GCs. In three patients, TSC2 locus mutations were confirmed and the mean tuberin mRNA expression levels was reduced across all nine cases. Consistent with these observations, NT3 mRNA expression was reduced but trkC mRNA expression was increased in vitro in human NTera2 neurons ( Tubers in the tuberous sclerosis complex (TSC) are developmental abnormalities of cerebral cortical cytoarchitecture that are associated clinically with epilepsy. [1][2][3] Electrocorticography has shown that tubers are epileptogenic and seizures in TSC patients are often medically intractable despite anticonvulsant polytherapy. 4 -6 TSC is an autosomal-dominant disorder resulting from mutations in one of two genes, TSC1 or TSC2 7,8 although the mechanism by which mutations in either TSC gene leads to tuber formation is unknown. Disorganized cortical lamination and aberrant cellular morphology are important histological features of tubers. Large dysplastic neurons (DNs) and giant cells (GCs) are prominent cell types in tubers. 9 DNs and GCs share select morphological features including cytomegaly, the extension of aberrant processes often of unclear identity, ie, axons versus dendrites, and the expression of neural protein markers such as neurofilament and ␣-internexin. 1,9,10 The TSC2 knockout mouse 11 and the Eker rat strain 12 do not fully model human brain pathology in TSC, and thus, analysis of human tuber specimens provides the only direct avenue to study the mechanisms of tuber formation. One strategy to investigate the molecular pathogenesis of cytoarchitectural disorganization in tubers is to evaluate the expression of candidate genes and proteins in human tuber specimens that are relevant to cortical development. 10 Neurotrophins and their cognate receptors comprise a family of proteins that mediate proliferation, differentiation, migration, and process outgrowth during cortical development, 13,14 and thus, are ideal candidate molecules to investigate in tubers. Brainderived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) exert their effects on neurons by binding selectively to a family of neuronal cell membrane receptors, trks A to C. 13,14 NGF signals...

show abstract

Section: Altered Neurotrophin Expression and Aberrant Cytoarchitecturmentioning

confidence: 99%

Section: Neurotrophin Expression Epilepsy and Epileptogenesismentioning

confidence: 99%

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Kyin

Yang

Baybis

et al. 2001

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…In this regard, the TrkB receptor can be activated by BDNF, NT3 and NT4 (also known as Ntf5 -Mouse Genome Informatics) (Huang and Reichardt, 2003), and whereas previous work (Jones et al, 1994;Alcantara et al, 1997;Ringstedt et al, 1998;Xu et al, 2000;Lotto et al, 2001;Medina et al, 2004) has indicated that BDNF-mediated TrkB activation is important for cortical development in vivo, these studies concluded that any observed perturbations were a consequence of altered TrkB signaling in cortical neurons. The TrkC receptor is only activated by NT3, and previous work on Nt3 -/-and TrkC -/-mice has primarily focused upon the profound deficits observed in the peripheral nervous system (Ernfors et al, 1994;Wilkinson et al, 1996;Klein et al, 1994;Tessarollo et al, 1994), or on perturbations in the biology of committed CNS glia or neurons (Minichiello and Klein, 1996;Martinez et al, 1998;Kahn et al, 1999;Ma et al, 2002;von Bohlen und Halbach et al, 2003). As both BDNF and NT3 are known to be expressed in precursor cells of the cortical neuroepithelium (Maisonpierre et al, 1990;Fukumitsu et al, 1998;Behar et al, 1997;Barnabé-Heider and Miller, 2003;Fukumitsu et al, 2006), and as cortical precursors express both of these receptors (Tessarollo et al, 1993;Behar et al, 1997;Barnabé-Heider and Miller, 2003), we have chosen to disrupt signaling via these two receptors both individually and together.…”

Section: Introductionmentioning

confidence: 99%

Trk signaling regulates neural precursor cell proliferation and differentiation during cortical development

et al. 2007

View full text Add to dashboard Cite

Increasing evidence indicates that development of embryonic central nervous system precursors is tightly regulated by extrinsic cues located in the local environment. Here, we asked whether neurotrophin-mediated signaling through Trk tyrosine kinase receptors is important for embryonic cortical precursor cell development. These studies demonstrate that inhibition of TrkB (Ntrk2) and/or TrkC (Ntrk3) signaling using dominant-negative Trk receptors, or genetic knockdown of TrkB using shRNA, caused a decrease in embryonic precursor cell proliferation both in culture and in vivo. Inhibition of TrkB/C also caused a delay in the generation of neurons, but not astrocytes, and ultimately perturbed the postnatal localization of cortical neurons in vivo. Conversely, overexpression of BDNF in cortical precursors in vivo promoted proliferation and enhanced neurogenesis. Together, these results indicate that neurotrophin-mediated Trk signaling plays an essential, cell-autonomous role in regulating the proliferation and differentiation of embryonic cortical precursors and thus controls cortical development at earlier stages than previously thought.

show abstract

“…Recent evidence indicates roles for neurotrophin-3 and colony stimulating factor-1 (CSF-1), which are expressed in the developing brain. (Michaelson et al, 1996;Calvo et al, 1998;Wegiel et al, 1998;Kahn et al, 1999).…”

mentioning

confidence: 99%

Regulation of Microglial Development: A Novel Role for Thyroid Hormone

et al. 2001

View full text Add to dashboard Cite

The postnatal development of rat microglia is marked by an important increase in the number of microglial cells and the growth of their ramified processes. We studied the role of thyroid hormone in microglial development. The distribution and morphology of microglial cells stained with isolectin B4 or monoclonal antibody ED1 were analyzed in cortical and subcortical forebrain regions of developing rats rendered hypothyroid by prenatal and postnatal treatment with methyl-thiouracil. Microglial processes were markedly less abundant in hypothyroid pups than in age-matched normal animals, from postnatal day 4 up to the end of the third postnatal week of life. A delay in process extension and a decrease in the density of microglial cell bodies, as shown by cell counts in the developing cingulate cortex of normal and hypothyroid animals, were responsible for these differences. Conversely, neonatal rat hyperthyroidism, induced by daily injections of 3,5,3Ј-triiodothyronine (T3), accelerated the extension of microglial processes and increased the density of cortical microglial cell bodies above physiological levels during the first postnatal week of life.Reverse transcription-PCR and immunological analyses indicated that cultured cortical ameboid microglial cells expressed the ␣1 and ␤1 isoforms of nuclear thyroid hormone receptors. Consistent with the trophic and morphogenetic effects of thyroid hormone observed in situ, T3 favored the survival of cultured purified microglial cells and the growth of their processes. These results demonstrate that thyroid hormone promotes the growth and morphological differentiation of microglia during development.

show abstract

Mice lacking NT-3, and its receptor TrkC, exhibit profound deficiencies in CNS glial cells

Cited by 89 publications

References 56 publications

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Trk signaling regulates neural precursor cell proliferation and differentiation during cortical development

Regulation of Microglial Development: A Novel Role for Thyroid Hormone

Contact Info

Product

Resources

About