Development of the mouse hypothalamo‐neurohypophysial system in the munc18–1 null mutant that lacks regulated secretion

Korteweg, Niki; Maia, Ascanio S.; Verhage, Matthijs; Burbach, J. Peter H.

doi:10.1111/j.0953-816x.2004.03383.x

Cited by 6 publications

(4 citation statements)

References 38 publications

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“…In analogy with this, in the absence of regulated secretion the hypothalamo-neurohypophysial system is initially normally formed, but in later stages of development degenerates [19]. This is consistent with our observation that Munc18-1 is dispensable for initial generation and outgrowth of 5-HT neurons, but required for their survival.…”

Section: Discussionsupporting

confidence: 91%

Deletion of Munc18-1 in 5-HT Neurons Results in Rapid Degeneration of the 5-HT System and Early Postnatal Lethality

et al. 2011

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The serotonin (5-HT) system densely innervates many brain areas and is important for proper brain development. To specifically ablate the 5-HT system we generated mutant mice carrying a floxed Munc18-1 gene and Cre recombinase driven by the 5-HT-specific serotonin reuptake transporter (SERT) promoter. The majority of mutant mice died within a few days after birth. Immunohistochemical analysis of brains of these mice showed that initially 5-HT neurons are formed and the cortex is innervated with 5-HT projections. From embryonic day 16 onwards, however, 5-HT neurons started to degenerate and at postnatal day 2 hardly any 5-HT projections were present in the cortex. The 5-HT system of mice heterozygous for the floxed Munc18-1 allele was indistinguishable from control mice. These data show that deletion of Munc18-1 in 5-HT neurons results in rapid degeneration of the 5-HT system and suggests that the 5-HT system is important for postnatal survival.

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Section: Discussionsupporting

confidence: 91%

Deletion of Munc18-1 in 5-HT Neurons Results in Rapid Degeneration of the 5-HT System and Early Postnatal Lethality

et al. 2011

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“…The somata of these neurons are located in the paraventricular and supraoptical nuclei of the hypothalamus and these neurons have started to degenerate at E18 (see Verhage et al, 2000). Apparently, their axons that project to the neural lobe have disappeared and have been replaced by pituicytes (Korteweg et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

The role of Munc18‐1 in docking and exocytosis of peptide hormone vesicles in the anterior pituitary

Korteweg

Maia

Thompson

et al. 2005

Biology of the Cell

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Background information. Many neurons secrete classical transmitters from synaptic vesicles as well as peptide transmitters from LDCVs (large dense-core vesicles). Little is known about the mechanistic differences between these two secretory pathways. The soluble protein Munc18-1 is essential for synaptic vesicle secretion [Verhage, Maia, Plomp, Brussaard, Heeroma, Vermeer, Toonen, Hammer, van den Berg, Missler, et al. (2000) Science 287, 864-869.].Results. In the present study, we tested if Munc18 genes are also involved in peptidergic secretion from LDCVs using the anterior pituitary as a model system. We show that Munc18-1 is the dominant isoform expressed in the anterior pituitary. In Munc18-1 null mutant mice, the anterior pituitary developed normally and the five major endocrine cell types had a normal distribution. However, circulating peptide hormone levels were decreased by up to 50-fold in the null mutant, whereas the intracellular levels were significantly higher than that in controls. Ultrastructural analysis using the tannic acid method revealed striking differences in the distribution of secretory vesicles: (i) the number of exocytotic figures was mostly decreased in the null mutants and (ii) the LDCVs accumulated near but not at their target membrane. This is in contrast with the apparently normal distribution of synaptic vesicles in developing synapses in the null mutant (Verhage et al., 2000). Conclusions.We conclude that Munc18-1 is involved in the secretion of peptide hormones and in the docking of LDCVs. These results unmask an apparent mechanistic difference between LDCVs and synaptic vesicles.

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“…Particularly remarkable was the finding that targeted disruption of the mouse Munc18-1 gene produced a mutant that died shortly after birth (6). Even though brain development appeared normal, embryos from these mouse mutants were paralyzed due to the complete absence of both spontaneous and evoked synaptic transmission (6,44). However, analyses in neuroendocrine chromaffin cells from Munc18-1 null embryos demonstrated a small but significant evoked secretion of catecholamines (45).…”

Section: Discussionmentioning

confidence: 99%

Munc18-1 and Munc18-2 Proteins Modulate β-Cell Ca2+ Sensitivity and Kinetics of Insulin Exocytosis Differently

Mandic

Skelin

Johansson

et al. 2011

Journal of Biological Chemistry

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Fast neurotransmission and slower hormone release share the same core fusion machinery consisting of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. In evoked neurotransmission, interactions between SNAREs and the Munc18-1 protein, a member of the Sec1/Munc18 (SM) protein family, are essential for exocytosis, whereas other SM proteins are dispensable. To address if the exclusivity of Munc18-1 demonstrated in neuroexocytosis also applied to fast insulin secretion, we characterized the presence and function of Munc18-1 and its closest homologue Munc18-2 in ␤-cell stimulus-secretion coupling. We show that pancreatic ␤-cells express both Munc18-1 and Munc18-2. The two Munc18 homologues exhibit different subcellular localization, and only Munc18-1 redistributes in response to glucose stimulation. However, both Munc18-1 and Munc18-2 augment glucose-stimulated hormone release. To maintain glucose homeostasis in the body, the pancreatic ␤-cell must in a controlled way produce, store, and secrete insulin in response to appropriate stimuli (1). Regulated membrane fusion resulting in insulin exocytosis in ␤-cells is managed by the same core SNARE 3 (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) fusion machinery that mediates release of chemical signals at highly specialized central neuronal synapses (2-4). Three conserved SNARE proteins, VAMP2, syntaxin 1A, and SNAP-25, connect vesicles with the plasma membrane by forming an exceptionally stable protein complex that holds the intrinsic, but slow, capability to perform lipid bilayer fusion (5). Except for the SNARE proteins, additional cooperating proteins are critical to guarantee speed and accuracy of diverse membrane fusion events occurring in excitable cells. Such a key accessory regulator in synaptic transmission is Munc18-1, a member of the Munc18 (mammalian homologue of the unc-18 gene) family (6). In addition to Munc18-1 (with two alternatively spliced variants, Munc18-1a and Munc18-1b), Munc18-2 and Munc18-3 isoforms have also been identified (7-9). Munc18-2, also named Munc18b or muSec1 (mammalian ubiquitously Sec1), is the closest homologue of Munc18-1, showing 63% amino acid sequence identity (7).The 67-kDa hydrophilic Munc18-1 protein has been shown to be necessary not only for vesicle exocytosis but also for docking of vesicles to the plasma membrane (10). Indeed, in the absence of Munc18-1 in neuronal cells, neither evoked nor spontaneous neurotransmission can operate (6). However, besides the reported positive effect of Munc18-1 in regulated exocytosis (6, 11-13), Munc18-1 has also been identified as a negative regulator of insulin secretion (14, 15). Still, Munc18-1 is primarily considered to be a neuronal protein, whereas the homologue Munc18-2 has a wider tissue expression profile. For instance, Munc18-2 is prominent in epithelial cells (16) and has been identified as a binding partner of Cab45, a Ca 2ϩ -binding protein prominent in pancreatic acini (17). Recently Cab45/ Munc18-2 was a...

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Development of the mouse hypothalamo‐neurohypophysial system in the munc18–1 null mutant that lacks regulated secretion

Cited by 6 publications

References 38 publications

Deletion of Munc18-1 in 5-HT Neurons Results in Rapid Degeneration of the 5-HT System and Early Postnatal Lethality

Deletion of Munc18-1 in 5-HT Neurons Results in Rapid Degeneration of the 5-HT System and Early Postnatal Lethality

The role of Munc18‐1 in docking and exocytosis of peptide hormone vesicles in the anterior pituitary

Munc18-1 and Munc18-2 Proteins Modulate β-Cell Ca2+ Sensitivity and Kinetics of Insulin Exocytosis Differently

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