1,721,035 research outputs found
Kallmann's syndrome, a neuronal migration defect
No full textInfertility and inability to smell are the phenotypical features of Kallmann's syndrome (KS), a genetic disease which affects 1 in 10,000 males and 1 in 50,000 females, the majority of the cases being sporadic. The molecular pathogenesis of KS is complex but mainly referable to the impairment of olfactory axon development and of the migration of gonadotropin-releasing hormone (GnRH) neurons. Only two different genes have been identified so far as responsible for the disease: KAL1 and KAL2, encoding anosmin-1 and fibroblast growth factor receptor 1 (FGFR1), respectively. In this review we focus our attention on insights evoked by recent studies, which propose a new direct role for anosmin-1 in the migration GnRH neurons, and a fascinating hypothesis of interactions between anosmin-1 and FGFR1 systems
F1000Prime Recommendation of [Young J et al., Hum Reprod 2012]
No full textDespite several genes having been found mutated in patients affected by Kallmann's syndrome (KS) and hypogonadotropic hypogonadism (HH), the majority of cases (>60%) still has no causative gene, suggesting that additional disease loci remain to be identified. The discovery of the involvement of the semaphorin 3A (SEMA3A) gene in KS is of great value for a better genetic framework and counselling of the disease.
In this research article, the authors report that a heterozygous deletion in the SEMA3A gene cosegregates with a KS phenotype. SEMA3A belongs to the class 3 semaphorins, a family of secreted molecules that modulate axonal guidance and neuronal migration events in the developing nervous system, and exert their actions by binding to neuropilins (NRP1 and NRP2) and plexins. Recently, by combining the analysis of genetically altered mice with in vitro models, we reported an essential role of SEMA3A in the development of the gonadotropin-releasing hormone (GnRH) neurons (see {1}, on which we are both authors), the population of hypothalamic neurons that exerts the physiological control of the reproductive axis. A defect in migration of GnRH neurons has been involved in the pathogenesis of the X-linked form of KS. Strikingly, mice lacking SEMA3A, or its signalling through both NRP1 and NRP2, recapitulate the anatomical features of altered GnRH neuron migration observed in KS.
Therefore, this report is an important clinical confirmation of results obtained in animal and cell models. On the other hand, the defects observed in mice may be suggestive of an impairment of GnRH neuron migration also in this KS patient. These results indicate that genomic sequencing analysis and studies on animal/cell models of KS/HH may synergistically interact to lead to a better elucidation of the pathogenesis of these diseases. The findings reported in the study have a broad significance in the search of new candidate genes responsible for more than 60% of the idiopathic forms of HHs. SEMA3A gene analysis must be included in the genetic screening of idiopathic HH.
References
1.
Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism.
Cariboni A, Davidson K, Rakic S, Maggi R, Parnavelas JG, Ruhrberg C Hum Mol Genet 2011 Jan 15; 2(20):336-44
PMID: 2105970
The Hormone of Love Attracts a Partner for Life
No full textNeurovascular integration during embryonic development is essential for adult physiology. In this issue of Developmental Cell, Gutnick et al. (2011) report that hypothalamic neurons secrete oxytocin as a guidance cue for endothelial cells to establish their vascular supply—a prerequisite for neuroendocrine secretion from the neurohyophysis in adult life
The role of semaphorin signaling in the etiology of hypogonadotropic hypogonadism
No full textIn mammals fertility depends on timely onset and cyclic secretion of gonadotropin-releasing hormone (GnRH), secreted by scattered hypothalamic neurons (GnRH neurons). These cells originate in the nasal placode and migrate first in the nasal compartment, then through the cribriform plate and finally across the basal forebrain, before they set in their final position in the hypothalamus. This long journey is regulated by many different factors that could be mutated in neuroendocrine syndromes such as congenital hypogonadotropic hypogonadism (CHH), Kallmann Syndrome (KS) and CHARGE syndrome. Recently, semaphorins, a large family of molecules, previously discovered as axon guidance cues, are emerging as key regulators of the neuroendocrine control of GnRH neurons and are acquiring an increasing role in the etiopathogenesis of CHH and KS. Specifically, semaphorins play a multifaceted action in GnRH neuron biology: on one hand regulating their migration and survival during embryonic development and, on the other, controlling the plasticity of the median eminence (ME) in terms of its response to varying sex steroid hormone levels. In this review we will focus our attention on recent studies describing the roles of different semaphorins in the normal and pathological biology of the GnRH neuronal system
LOW EXPRESSION OF SELADIN-1/DHCR24 GENE CONFERS RESISTANCE TO TOXIC INSULTS IN IMMATURE GnRH NEURONS
No full textCholesterol is essential for the correct development of the central nervous system. Recently, a new gene termed "SELective Alzheimer's Disease INdicator 1" (Seladin-1, sel-1) was characterized as coding for a cholesterol-biosynthetic enzyme 3beta-hydroxysterol delta24-reductase (DHCR24), whose mutations lead to tissue cholesterol depletion, and desmosterol accumulation. Moreover, it has been proposed that sel-1 gene product may exert prosurvival and antiapoptotic actions. Surprisingly, sel-1 null mice are viable but infertile, possibly due to a lack of sex steroids. However, the assessed actions of sel-1 on neuronal function lead to hypothesize a role also in the development/function of GnRH neurons. Cell lines of mature (GT1-7) and immature (GN11) GnRH neurons were then used for in vitro experiments. In previous experiments we found that GT1-7 cells present 100 times higher expression of sel-1 compared to GN11 cells. Nevertheless, no difference were observed between the two cell lines in term of Sel-1 immunoreactivity, distributed around the nucleus associated by endoplasmic reticulum, and of proliferation rate after removal of exogenous cholesterol. However the total sterol content in the absence of exogenous cholesterol was higher in GT1-7 cells and a different accumulation of free cholesterol, detected by filipin staining, was also observed. GT1-7 cells have been found to be more sensitive to desmosterol and cholesterol toxicity and to induction of oxidative stress. Finally, the oxidative stress-induced decrease of sel-1 expression was significantly more evident in GT1-7 than GN11 cells. In conclusion, these data suggest that a) mature and immature GnRH neurons have a differential cholesterol synthesis/metabolism, b) immature GN11 neurons utilize part of the exogenous cholesterol; c) the possible major fraction of desmosterol in GN11 cells make them more resistant to toxic insults and d) the lower levels of sel-1 in immature GnRH cells may suggest a possible role as a mediator of toxic insult response in these neurons. Further studies are needed to determine the exact roles of desmosterol and sel-1 in the development of GnRH neuronal. (Grants: PRIN2005 # 2005051740
Role of VEGF and blood vessels during GnRH-neurons development
No full textGonadotropin-releasing hormone (GnRH) neurons, a
small number of neuroendocrine cells scattered in the
hypothalamus, play an important role in reproduction.
During development, GnRH neurons are born in the
olfactory placode and migrate along olfactory nerves in
the nasal compartment to gain access into the forebrain
and reach the hypothalamus. In humans, defects in
their migration result in infertility. The mechanisms
involved in the migration of GnRH neurons are
under investigation. We have recently described that
classical guidance molecules, such neuropilins (NRPs),
are expressed by GnRH neurons, and established
the importance of NRP2 in their migration in vivo.
Using immortalised GnRH-neurons, we found that
two distinct NRP ligands regulate their migratory
response: the class 3 semaphorins and vascular
endothelial growth factor A (VEGF). VEGF is a major
regulator of vasculogenesis, interacting with receptor
tyrosine kinases (Flt-1/Flk-1) on endothelial cells.
Recent evidence indicates that VEGF has additional
non vascular-functions. In particular, VEGF can act
directly on neurons to produce different effects such
survival, axonal elongation and migration. In this
study, the interactions between blood vessels and
GnRH-system have been tested. Using RT-PCR and
enzymatic stainings of VEGF-LacZ reporter mice,
we found that VEGF is significantly expressed in the
nasal region during development. We also visualised
the presence of a network of blood vessels along the
migratory path of GnRH neurons. Moreover, isolated
mouse embryonic GnRH neurons express specific
transcripts for VEGF and Flt-1. Functionally, we found
that VEGF exerts pleiotropic effects on immortalised
GnRH-neurons, acting on survival, chemomigration
and axonal elongation. Taken together, these novel data
raise the possibility that GnRH neuronal migration
and development are modulated by VEGF signalling,
suggesting the existence of a cross-talk between
the vascular and GnRH-neuron system
Seladin-1/DHCR24 gene overexpression decreased migration of immature immortalized neurons
No full textDHCR24 (3beta-hydroxysterol delta24-reductase) is a key enzyme to form cholesterol from desmosterol; Interestingly, high levels of desmosterol are present during fetal brain development. DHCR24 is also called Seladin-1 (for Selective Alzheimer’s Disease Indicator-1, Sel-1) since it is down-regulated in the brain regions more susceptible to this disease. Moreover, it has been implicated in tumor progression, neuroprotection and oxidative stress, suggesting a prosurvival and antiapoptotic action.
In the present study we investigated the expression of Sel-1 in immortalized neurons derived from mature (GT1-7) and immature (GN11) endocrine neurons and a possible role in the neuronal maturation and motility. We found that GT1-7 cells present 100 times higher levels of Sel-1 mRNA and protein compared to GN11 cells as well as a different intracellular distribution. Accordingly, an higher relative amount of desmosterol was present in GN11 cells. In a first series of functional experiments, we found that cyclodextrin-mediated membrane cholesterol/desmosterol substitution did not affect the motility of GN11 cells. By transfection of GN11 cells with a Seladin-1-GFP construct we observed an increase of the cholesterol and a decrease of the desmosterol content, a distribution of the protein similar to mature GT1-7 cells as well as a neurite growth stimulation. Moreover, by microchemotaxis assay, we found that transfected cells showed a decrease of their motility. In conclusions, these results are suggestive of a possible role of Seladin-1/DHCR24 on some event of neuronal development/differentiation, through a control of the intracellular cholesterol/desmosterol ratio
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