Flanking regulatory sequences of the locus encoding the murine GDNF receptor, <i>c</i>‐ret, directs lac Z (β‐galactosidase) expression in developing somatosensory system

Sukumaran, Madhu; Waxman, Stephen G.; Wood, John N.; Pachnis, Vassilis

doi:10.1002/dvdy.1192

Cited by 13 publications

(13 citation statements)

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“…A glutamate decarboxylase (GAD)67‐specific riboprobe was generated from a 1.1‐kb cDNA representing the 5′ region of the GAD67 coding sequence (a kind gift of F. Guillemot). β‐gal histochemistry was carried out essentially as described previously (Sukumaran et al ., 2001). To quantify the β‐gal‐, ChAT‐, TrkA‐ or GAD67‐expressing cells in the brain, we used serial brain cryosections (14 µm) from heterozygous Lhx7 +/ nLacZ and mutant Lhx7 nLacZ / nLacZ adult males.…”

Section: Methodsmentioning

confidence: 99%

Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7‐deficient mice

Fragkouli

Hearn²,

Errington³

et al. 2005

Eur J of Neuroscience

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The identification of the genetic determinants specifying neuronal networks in the mammalian brain is crucial for the understanding of the molecular and cellular mechanisms that ultimately control cognitive functions. Here we have generated a targeted allele of the LIM-homeodomain-encoding gene Lhx7 by replacing exons 3-5 with a LacZ reporter. In heterozygous animals, which are healthy, fertile and have no apparent cellular deficit in the forebrain, b-galactosidase activity reproduces the pattern of expression of the wild-type Lhx7 locus. However, homozygous mutant mice show severe deficits in forebrain cholinergic neurons (FCNs), while other classes of forebrain neurons appear unaffected. Using the LacZ reporter as a marker, we show that in LHX7-deficient mice FCN progenitors survive but fail to generate cholinergic interneurons in the striatum and cholinergic projection neurons in the basal forebrain. Analysis of behaviour in a series of spatial and non-spatial learning and memory tasks revealed that FCN ablation in Lhx7 mutants is associated with severe deficits in spatial but only mild impairment of non-spatial learning and memory. In addition, we found no deficit in long-term potentiation in mutant animals, suggesting that FCNs modulate hippocampal function independently of its capacity to store information. Overall our experiments demonstrate that Lhx7 expression is required for the specification or differentiation of cholinergic forebrain neurons involved in the processing of spatial information.

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Section: Methodsmentioning

confidence: 99%

Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7‐deficient mice

Fragkouli

Hearn²,

Errington³

et al. 2005

Eur J of Neuroscience

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“…Transgenic mice (CBA͞B6 strain) that constitutively overexpress galanin in the DRG were generated by using the previously described 12-kb flanking regulatory sequences of the murine c-Ret gene (41) to drive expression of the 4.6-kb galanin-coding region, inserted at the unique SacII site.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to the Gal-OE mice, we have also generated transgenic animals by using the previously described 12-kb c-Ret enhancer region (41) to drive the expression of the murine galanin gene (Ret-OE). This enhancer region recently has been demonstrated to target the IB4-binding neurons in the DRG (41), and expression of the transgene does not alter after axotomy (F.E.H., D.W., and V.P., unpublished data), consistent with the previously reported expression of c-Ret, a component of the GDNF receptor (45,46).…”

Section: Figmentioning

confidence: 99%

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Holmes

Bacon

Pope

et al. 2003

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

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The neuropeptide galanin is expressed in the dorsal root ganglia (DRG) and spinal cord and is thought to be involved in the modulation of pain processing. However, its mechanisms of action are complex and poorly understood, as both facilitatory and inhibitory effects have been described. To understand further the role played by galanin in nociception, we have generated two transgenic lines that overexpress galanin in specific populations of primary afferent DRG neurons in either an inducible or constitutive manner. In the first line, a previously defined enhancer region from the galanin locus was used to target galanin to the DRG (Gal-OE). Transgene expression recapitulates the spatial endogenous galanin distribution pattern in DRG neurons and markedly overexpresses the peptide in the DRG after nerve injury but not in the uninjured state. In the second line, an enhancer region of the c-Ret gene was used to constitutively and ectopically target galanin overexpression to the DRG (Ret-OE). The expression of this second transgene does not alter significantly after nerve injury. Here, we report that intact Ret-OE, but not Gal-OE, animals have significantly elevated mechanical and thermal thresholds. After nerve damage, using a spared nerve-injury model, mechanical allodynia is attenuated markedly in both the Gal-OE and Ret-OE mice compared with WT controls. These results support an inhibitory role for galanin in the modulation of nociception both in intact animals and in neuropathic pain states.T he neuropeptide galanin is widely distributed within the somatosensory system, where it has been implicated in the modulation of nociception (reviewed in refs. 1-3). In the adult dorsal root ganglia (DRG), galanin is expressed at relatively low levels in Ͻ5% of neurons that are predominantly small-diameter C fiber type (4). Expression of the peptide also is detected in the primary afferent terminals of the dorsal spinal cord and in subsets of dorsal horn interneurons (5). Galanin mRNA and peptide levels markedly increase in the DRG after axotomy and in several neuropathic pain models of sciatic nerve injury (4, 6-9). After axotomy, galanin is expressed in Ϸ40-50% of all DRG neurons (4, 10). In the dorsal horn, axotomy-induced galanin immunoreactivity increases in the afferent terminals, with a concurrent enhancement of synaptic release of the peptide (11).The role of galanin in pain signaling is complex (reviewed in refs. 2, 12, and 13). Electrophysiological and behavioral studies in the intact, uninjured peripheral nervous system have demonstrated both facilitatory (14-21) and inhibitory (22, 23) effects of exogenously applied galanin on nociception, sometimes in a modality-specific manner (14,16,20,21), tending toward inhibition at higher doses.A number of groups have used rodent models of neuropathic pain to study the role of galanin in the modulation of chronic pain behavior. The oldest and least understood pain model involves the scoring of autotomy behavior (self-mutilation of the denervated limb) after sciatic nerve a...

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“…It remains to be studied, whether Hes1 and Hes6 directly or indirectly regulate the expression of the GDNF receptor, but at least Ret promoter contains the binding sequence for Hes1 (nucleotides 3099-3105 in genebank accession number AY255629). However, the Ret promoter elements driving the expression to the developing kidney have not yet been characterised (Sukumaran et al, 2001).…”

Section: Hes1 Is Up-regulated In Jag1 Transgenic Wolffian Ductmentioning

confidence: 99%

Crosstalk between Jagged1 and GDNF/Ret/GFRα1 signalling regulates ureteric budding and branching

Kuure

Sainio

Vuolteenaho

et al. 2005

Mechanisms of Development

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Glial-Cell-Line-Derived Neurotrophic Factor (GDNF) is the major mesenchyme-derived regulator of ureteric budding and branching during nephrogenesis. The ligand activates on the ureteric bud epithelium a receptor complex composed of Ret and GFRalpha1. The upstream regulators of the GDNF receptors are poorly known. A Notch ligand, Jagged1 (Jag1), co-localises with GDNF and its receptors during early kidney morphogenesis. In this study we utilized both in vitro and in vivo models to study the possible regulatory relationship of Ret and Notch pathways. Urogenital blocks were exposed to exogenous GDNF, which promotes supernumerary ureteric budding from the Wolffian duct. GDNF-induced ectopic buds expressed Jag1, which suggests that GDNF can, directly or indirectly, up-regulate Jag1 through Ret/GFRalpha1 signalling. We then studied the role of Jag1 in nephrogenesis by transgenic mice constitutively expressing human Jag1 in Wolffian duct and its derivatives under HoxB7 promoter. Jag1 transgenic mice showed a spectrum of renal defects ranging from aplasia to hypoplasia. Ret and GFRalpha1 are normally downregulated in the Wolffian duct, but they were persistently expressed in the entire transgenic duct. Simultaneously, GDNF expression remained unexpectedly low in the metanephric mesenchyme. In vitro, exogenous GDNF restored the budding and branching defects in transgenic urogenital blocks. Renal differentiation apparently failed because of perturbed stimulation of primary ureteric budding and subsequent branching. Thus, the data provide evidence for a novel crosstalk between Notch and Ret/GFRalpha1 signalling during early nephrogenesis.

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Flanking regulatory sequences of the locus encoding the murine GDNF receptor, c‐ret, directs lac Z (β‐galactosidase) expression in developing somatosensory system

Abstract: RET forms the catalytic component within the receptor complex that transmits signals from the GDNF family of neurotrophic factors. To study the mechanisms regulating the cell-type specific expression of this gene, we have cloned and characterised the murine c-ret locus.

Cited by 13 publications

References 138 publications

Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7‐deficient mice

Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7‐deficient mice

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Crosstalk between Jagged1 and GDNF/Ret/GFRα1 signalling regulates ureteric budding and branching

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