Cholecystokinin Modulates Migration of Gonadotropin-Releasing Hormone-1 Neurons

Giacobini, Paolo; Kopin, Alan S.; Beart, Philip M; Mercer, Linda D; Fasolo, Aldo; Wray, Susan

doi:10.1523/jneurosci.0649-04.2004

Cited by 79 publications

(84 citation statements)

References 86 publications

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“…Nuclei were counterstained with DAPI (Sigma). When two polyclonal primary antibodies were used (antiGnRH/Npn-2), staining of the first antigen-antibody complex (GnRH) was visualized with a goat anti-rabbit Alexa Fluor 488 (1:400; Invitrogen) secondary antibody (Giacobini et al, 2004). This was followed by a blocking reaction with 10% normal rabbit serum (Sigma) at room temperature for 1 h, followed by washes in PBS plus 0.1% Triton X-100 and fixation (4% paraformaldehyde for 45 min), before application of the second primary antibody, which was visualized with goat anti-rabbit Alexa Fluor 594 (1:400; Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Cariboni¹,

Hickok²,

Rakić³

et al. 2007

J. Neurosci.

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Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus play an important role in reproductive function. These cells originate in the nasal compartment and migrate into the basal forebrain in association with olfactory/vomeronasal nerves in embryonic life in rodents. Here, we studied the role of neuropilins and their ligands, semaphorins, in the development of the olfactory-GnRH system. We focused on Neuropilin-2 knock-out (Npn-2 ؊/؊ ) mice, because they are known to display defasciculation of olfactory nerves and reduced fertility. We found a significant decrease in the number of GnRH neurons in the hypothalamus and a marked reduction in their gonadal size. We then observed an abnormal increase of GnRH neurons in the noses of Npn-2 ؊/؊ mice, indicating that these cells failed to migrate into the forebrain. However, because neuropilins and semaphorins are involved in events of neuronal migration in the brain, we asked whether the observed reduction in GnRH neurons was directly attributable to the action of these molecules. Using fluorescenceactivated cell sorting and reverse transcription-PCR on mRNA derived from embryonic green fluorescent protein (GFP)-GnRH transgenic mice, we found expression of class 3 semaphorins and their receptors (neuropilin-1/2 and plexin-A1) in GnRH neurons. Furthermore, double-immunofluorescence experiments showed that migrating GnRH neurons, as well as associated olfactory fibers, express Npn-2 in the nasal region. We then used a line of immortalized GnRH neurons (GN11 cells) that display the same expression patterns for semaphorins and their receptors as GFP-GnRH cells and found that class 3 semaphorins and vascular endothelial growth factors modulate their migratory activity. These studies provide support for the direct involvement of neuropilins and their ligands in the establishment of the GnRH neuroendocrine system.

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Section: Methodsmentioning

confidence: 99%

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Cariboni¹,

Hickok²,

Rakić³

et al. 2007

J. Neurosci.

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“…CCK modifies the migratory abilities, proliferation, and survival of tumor astrocytes (14) and lymphocytes (15) and guides migration of gonadotropin-releasing hormone-1 (GnRH-1) neuroendocrine neurons into the brain (16). Moreover, immortalized rat brain neuroblasts express CCK1-and CCK2R mRNAs, and exposure to CCK promotes proliferation and improves viability (17).…”

mentioning

confidence: 99%

Peptidergic influences on proliferation, migration, and placement of neural progenitors in the adult mouse forebrain

Stanić

Paratcha

Ledda

et al. 2008

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

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Neural progenitor proliferation, differentiation, and migration are continually ongoing processes in the subventricular zone (SVZ) and rostral migratory stream (RMS) of the adult brain. There is evidence that peptidergic systems may be involved in the molecular cascades regulating these neurogenic processes, and we examined a possible influence of neuropeptide Y (NPY) and cholecystokinin (CCK) systems in cell proliferation and neuroblast formation in the SVZ and RMS and generation of interneurons in the olfactory bulb (OB). We show that NPY and the Y1 and Y2 receptor (R) proteins are expressed in and surrounding the SVZ and RMS and that Y1R is located on neuroblasts in the anterior RMS. Mice deficient in Y1Rs or Y2Rs have fewer Ki-67-immunoreactive (ir) proliferating precursor cells and doublecortin-ir neuroblasts in the SVZ and RMS than WT mice, and less calbindin-, calretinin-, and tyrosine hydroxylase-ir interneurons in the OB. Mice lacking CCK1Rs have fewer proliferating cells and neuroblasts than normal and a shortage of interneurons in the OB. These findings suggest that both NPY and CCK through their receptors help to regulate the proliferation of precursor cells, the amount of neuroblast cells in the SVZ and RMS, and influence the differentiation of OB interneurons.adult neurogenesis ͉ CCK receptors ͉ neuropeptides ͉ NPY receptors ͉ rostral migratory stream T he mature mammalian nervous system arises from precisely coordinated proliferation, differentiation, and migration of precursor cells during embryonic and early postnatal development (1). In adulthood, neurogenesis is restricted to three regions: the subventricular or subependymal zone (SVZ) of the lateral ventricle, the olfactory bulb (OB), and in the subgranular zone (SGZ) of the dentate gyrus. In the adult, newborn cells in the SGZ (2) integrate into hippocampal circuitry and are associated with learning and memory formation (3), whereas neural progenitor cells in the SVZ migrate along the rostral migratory stream (RMS) to the center of the OB, where they radiate to become interneurons in granule, periglomerular, and external plexiform cell layers (4, 5).Cascades of molecular signals that underlie fate specification and migration of adult neural progenitors have begun to be clarified (6, 7), and peptidergic systems also appear to participate in these processes. Neuropeptide Y (NPY), which is widely expressed in the central and peripheral nervous system during development and adulthood, has been implicated in proliferation of neuronal precursor cells in olfactory regions and the SGZ. Mice with targeted deletion of NPY (8) contain half as many dividing olfactory neuronal precursor cells as normal and fewer olfactory neurons by adulthood (9), likely mediated through the Y1 receptor (R) subtype (9, 10). This is supported by in vivo work showing that the dentate gyrus of mice lacking Y1Rs has significantly reduced cell proliferation and fewer immature neurons (11,12). Our recent observation of strong Y2R protein expression in a tract immediately along...

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“…At two time points [4.5 and 28 d in vitro (div)], single GnRH-1 cells (n ϭ 5 for each in vitro stage) were isolated from nasal explants using a micropipette (see Fig. 4 A-C) controlled by a micromanipulator (Narishige, Tokyo, Japan) connected to an inverted microscope (IX51; Olympus Optical, New Hyde Park, NY), cDNA was produced, and PCR amplification was performed as described previously Giacobini et al, 2004). Briefly, a single cell was lysed and reverse transcribed [AMV (avian myeloblastosis virus) and MMLV (Moloney murine leukemia virus)-reverse tran-scriptases; 37°C for 15 min; 65°C for 10 min] using an oligo-dT primer (50 OD/ml; pd(T) 19 -24 ).…”

Section: Cell Isolation and Pcr Analysismentioning

confidence: 99%

“…This step was followed by a blocking reaction with an anti-rabbit Fab fragment (Jackson ImmunoResearch Laboratories, West Grove, PA) (Giacobini et al, 2004) for 1 h (RT), followed by PBS washes, fixation (4% formalin for 30 min), and more PBS washes before application of the second primary antibody, which was visualized with conjugated fluorescent goat anti-rabbit cyanine 3 (Cy3; 1:800; Jackson ImmunoResearch Laboratories).…”

Section: Immunocytochemistrymentioning

confidence: 99%

“…Factors already shown to influence GnRH-1 neuron migration, either directly or indirectly via extension of olfactory axons (Wray, 2002;Wierman et al, 2004;Tobet and Schwarting, 2006), include neurotransmitters/neuropeptides (Fueshko et al, 1998;Bless et al, 2000;Simonian and Herbison, 2001;Pronina et al, 2003;Giacobini et al, 2004), surface molecules (Yoshida et al, 1999;Gamble et al, 2005), and growth factors (Cronin et al, 2004;Gill et al, 2004;Gill and Tsai, 2006). Guidance of the axonal/migratory pathway is also an important prerequisite for establishment of the adult-like GnRH-1 cell distribution (Wray, 2002), and classical chemoattractants [(e.g., netrin-1 and stromal cell-derived factor-1 (SDF-1)] or chemorepellents (e.g., reelin) are distributed in gradients along the GnRH-1 migratory route and participate in directing appropriate migration (Schwarting et al, 2001(Schwarting et al, , 2004Cariboni et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte Growth Factor Acts as a Motogen and Guidance Signal for Gonadotropin Hormone-Releasing Hormone-1 Neuronal Migration

Giacobini

Messina²,

Wray³

et al. 2007

J. Neurosci.

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Reproduction in mammals is under the control of the hypothalamic neuropeptide gonadotropin hormone-releasing hormone-1 (GnRH-1). GnRH-1-secreting neurons originate during embryonic development in the nasal placode and migrate into the forebrain along olfactory nerves. Gradients of secreted molecules may play a role in this migratory process. In this context, hepatocyte growth factor (HGF) is a potential candidate, because it promotes cell motility in developing brain and has been shown previously to act as a motogen on immortalized GnRH-1 neurons (GN11). In this study, the role of HGF and its receptor Met during development of the GnRH-1 system was examined. GnRH-1 cells express Met during their migration and downregulate its expression once they complete this process. Tissue-type plasminogen activator (tPA), a known HGF activator, is also detected in migratory GnRH-1 neurons. Consistent with in vivo expression, HGF is present in nasal explants, and GnRH-1 neurons express Met. HGF-neutralizing antibody was applied to explants to examine the role of the endogenous growth factor. Migration of GnRH-1 cells and olfactory axon outgrowth were significantly reduced, in line with disruption of a guidance gradient. Exogenous application of HGF to explants increased the distance that GnRH-1 cells migrated, suggesting that HGF also acts as a motogen to GnRH-1 neurons. Functional experiments, performed on organotypic slice cultures, show that creation of an opposing HGF gradient inhibits GnRH-1 neuronal migration. Finally, tPA Ϫ/Ϫ :uPA Ϫ/Ϫ (urokinase-type plasminogen activator Ϫ/Ϫ ) knock-out mice exhibit strong reduction of the GnRH-1 cell population. Together, these data indicate that HGF signaling via Met receptor influences the development of GnRH-1.

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Cholecystokinin Modulates Migration of Gonadotropin-Releasing Hormone-1 Neurons

Cited by 79 publications

References 86 publications

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Peptidergic influences on proliferation, migration, and placement of neural progenitors in the adult mouse forebrain

Hepatocyte Growth Factor Acts as a Motogen and Guidance Signal for Gonadotropin Hormone-Releasing Hormone-1 Neuronal Migration

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