The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons

Cariboni, Anna; Pimpinelli, Federica; Colamarino, Sophia A.; Zaninetti, Roberta; Piccolella, Margherita; Rumio, Cristiano; Piva, F.; Rugarli, Elena I.; Maggi, Roberto

doi:10.1093/hmg/ddh309

Cited by 125 publications

(125 citation statements)

References 58 publications

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“…6a). Anosmin-1-GFP also showed a punctate pattern on the cell periphery and within the cytoplasm, indicating accumulation along the plasma membrane as well as within the endosomal vesicles, as expected from an extracellular matrixassociated secretory protein, and also consistent with a previous report (34). When FGFR1 and anosmin-1-GFP images were overlaid, there was considerable overlap of the FGFR1 staining with the GFP (marked with arrows in Fig.…”

Section: Volume 284 • Number 43 • October 23 2009supporting

confidence: 89%

See 1 more Smart Citation

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Guimond

Travers

et al. 2009

Journal of Biological Chemistry

101

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Activation of fibroblast growth factor (FGF) signaling is initiated by a multiprotein complex formation between FGF, FGF receptor (FGFR), and heparan sulfate proteoglycan on the cell membrane. Cross-talk with other factors could affect this complex assembly and modulate the biological response of cells to FGF. We have previously demonstrated that anosmin-1, a glycosylated extracellular matrix protein, interacts with the FGFR1 signaling complex and enhances its activity in an IIIc isoformspecific and HS-dependent manner. The molecular mechanism of anosmin-1 action on FGFR1 signaling, however, remains unknown. Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. This interaction involves domains in the N terminus of anosmin-1 (cysteine-rich region, whey acidic protein-like domain and the first fibronectin type III domain) and the D2-D3 extracellular domains of FGFR1. In contrast, anosmin-1 binds to FGFR2IIIc with much lower affinity and displays negligible binding to FGFR3IIIc. We also show that FGFR1-bound anosmin-1, although capable of binding to FGF2 alone, cannot bind to a FGF2⅐heparin complex, thus preventing FGFR1⅐FGF2⅐heparin complex formation. By contrast, heparinbound anosmin-1 binds to pre-formed FGF2⅐FGFR1 complex, generating an anosmin-1⅐FGFR1⅐FGF2⅐heparin complex. Furthermore, a functional interaction between anosmin-1 and the FGFR1 signaling complex is demonstrated by immunofluorescence co-localization and Transwell migration assays where anosmin-1 was shown to induce opposing effects during chemotaxis of human neuronal cells. Our study provides molecular and cellular evidence for a modulatory action of anosmin-1 on FGFR1 signaling, whereby binding of anosmin-1 to FGFR1 and heparin can play a dual role in assembly and activity of the ternary FGFR1⅐FGF2⅐heparin complex. FGF5 signaling plays an important role in a wide range of fundamental biological responses (1-3). Both FGF and FGFR bind to heparan sulfate (HS) and heparin, a highly sulfated type of HS produced in connective tissue mast cells. Heparan sulfate proteoglycans (HSPG) are the cell surface co-receptors essential for the formation of functional FGF⅐FGFR signaling complex (4, 5). There are four structurally related FGFRs (FGFR1-4), which consist of an extracellular ligand-binding region containing three immunoglobulin (Ig)-like domains (D1-D3), a single transmembrane domain, and a cytoplasmic domain with protein-tyrosine kinase catalytic activity. The 22 members of the FGF family bind to the interface formed by the D2/D3 domains and the linker between these domains (6, 7), whereas a conserved positively charged region in D2 serves as the HS binding site (8). An unusual stretch of seven to eight acidic residues designated as the "acid box" is present in the linker connecting D1 and D2. Alternative splicing events occur to generate various isoforms, including a truncated receptor lacking D1 and the D1-D2 linker or a full-length receptor that differs in the second half of D3, designated as IIIb and IIIc isoforms (5). Two cry...

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Section: Volume 284 • Number 43 • October 23 2009supporting

confidence: 89%

“…Anosmin-1 and FGFR1 are known to be involved in GnRH neuron migration and neurite outgrowth (25,34,44,45). We now report that anosmin-1 can function as a chemoattractant inducing migration of immortalized FNC-B4-hTERT cells via an FGFR1-and HS-dependent mechanism (Fig.…”

Section: Discussionmentioning

confidence: 99%

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Guimond

Travers

et al. 2009

Journal of Biological Chemistry

101

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“…GN11 cells show a strong chemomigratory response in vitro (Maggi et al, 2000) and, as such, they have been used to investigate mechanisms involved in GnRH neuron migration (Giacobini et al, 2002;Cariboni et al, 2004Cariboni et al, , 2005. We first performed expression studies on GN11 cells to confirm our in vivo observations.…”

Section: Semaphorins and Neuropilins Are Involved In The Migration Ofmentioning

confidence: 85%

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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“…In the past decade, several genes have been implicated in the pathophysiology of IHH, establishing distinct physiological pathways. The first gene to be identified was KAL1 (9, 10); the protein it encodes, anosmin, plays guidance roles in (i) axonal outgrowth/branching from the olfactory bulb (18) and (ii) the migratory activity of GnRH neurons (19). Anosmin may also act as a co-ligand modulator of fibroblast growth factor receptor 1 (FGFR1) (20), whose parent gene has also been identified as harboring mutations in familial Kallmann syndrome (8).…”

Section: Discussionmentioning

confidence: 99%

Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism

et al. 2006

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Objective: To determine the frequency of rare nucleotide variants in GNRHR and GPR54 in a large cohort of probands (nZ166) with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), characterized by mode of inheritance, testicular volume, and presence or absence of endogenous LH pulsations. Methods: Whenever possible, probands answered detailed questionnaires, underwent full physical exams, and underwent q 10-min frequent blood sampling for LH. Exons segments for GNRHR and GPR54 were screened for mutations. Nucleotide changes were identified as rare variants if they occurred at less than 1% frequency in an ethnically matched control population. Results: Sixty-two percent of male probands were classified as sporadic, meaning that no other family members had delayed puberty or nIHH. In contrast, 61% of female probands were from familial pedigrees, with either autosomal dominant or autosomal recessive inheritance. Patients displayed a broad spectrum of disease severity based on testicular size and endogenous LH pulsations. Twenty-four rare variants were identified in GNRHR (within 15 probands) and seven rare variants in GPR54 (within five probands). Conclusions: Rare variants in GNRHR are more common than GPR54 in a nIHH population.European Journal of Endocrinology 155 S3-S10

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The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons

Cited by 125 publications

References 58 publications

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

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

Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism

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