Immunohistochemical relationships of huntingtin-associated protein 1 with enteroendocrine cells in the pyloric mucosa of the rat stomach

Yanai, Akie; Islam, Nabiul; Hayashi-Okada, Maki; Jahan, Mir Rubayet; Tarif, Abu Md Mamun; Nozaki, Kanako; Masumoto, Kouji; Shinoda, Koh

doi:10.1016/j.acthis.2020.151650

Cited by 9 publications

(7 citation statements)

References 47 publications

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“…HAP1 (huntingtin-associated protein) is a neuronal protein involved in vesicle trafficking selectively expressed in antral G cells but not D cells, enterochromaffin (EC) or enterochromaffin-like (ECL) cells. 36 Thus, both the 'discovery' data set and 'validation' cohort from the GEO profiles demonstrated a high degree of concurrence and underscored genes unique to DGASTs.…”

Section: Validation Using Gep-netsmentioning

confidence: 95%

Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours

Rico

Duan

Pandey

et al. 2021

BMJ Open Gastroenterol

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ObjectiveGastroenteropancreatic neuroendocrine tumours (GEP-NETs) encompass a diverse group of neoplasms that vary in their secretory products and in their location within the gastrointestinal tract. Their prevalence in the USA is increasing among all adult age groups.AimTo identify the possible derivation of GEP-NETs using genome-wide analyses to distinguish small intestinal neuroendocrine tumours, specifically duodenal gastrinomas (DGASTs), from pancreatic neuroendocrine tumours.DesignWhole exome sequencing and RNA-sequencing were performed on surgically resected GEP-NETs (discovery cohort). RNA transcript profiles available in the Gene Expression Omnibus were analysed using R integrated software (validation cohort). Digital spatial profiling (DSP) was used to analyse paraffin-embedded GEP-NETs. Human duodenal organoids were treated with 5 or 10 ng/mL of tumor necrosis factor alpha (TNFα) prior to qPCR and western blot analysis of neuroendocrine cell specification genes.ResultsBoth the discovery and validation cohorts of small intestinal neuroendocrine tumours induced expression of mesenchymal and calcium signalling pathways coincident with a decrease in intestine-specific genes. In particular, calcium-related, smooth muscle and cytoskeletal genes increased in DGASTs, but did not correlate with MEN1 mutation status. Interleukin 17 (IL-17) and tumor necrosis factor alpha (TNFα) signalling pathways were elevated in the DGAST RNA-sequencing. However, DSP analysis confirmed a paucity of immune cells in DGASTs compared with the adjacent tumour-associated Brunner’s glands. Immunofluorescent analysis showed production of these proinflammatory cytokines and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) by the tumours and stroma. Human duodenal organoids treated with TNFα induced neuroendocrine tumour genes, SYP, CHGA and NKX6.3.ConclusionsStromal–epithelial interactions induce proinflammatory cytokines that promote Brunner’s gland reprogramming.

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Section: Validation Using Gep-netsmentioning

confidence: 95%

Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours

Rico

Duan

Pandey

et al. 2021

BMJ Open Gastroenterol

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“…In identifying molecular features unique to the tumor-naïve hyperplastic antrum, we focused on a subset of genes enriched in our study and previously reported to be upregulated in human duodenal gastrinomas (DGASTs), including Hap1, Mn1 , and Uchl1 [60] . Among these, the neuronal protein Huntingtin-associated protein (Hap1) is also expressed by enteroendocrine cells (EECs) within the GI tract and was recently reported to be expressed in G cells but not in other EEC lineages of the pyloric antrum [61] . This is consistent with our observation of increased Hap1 gene expression and higher antral gastrin and Grp expression levels.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that transplanted human antral organoids co-cultured with human ENCCs induced the formation of highly differentiated epithelium analogous to the Brunner’s glands [66] . Subsequent analysis of ENCCs identified elevated expression of the Shh-induced posteriorizing factors Bmp4 and Bmp7, and inhibition of these factors in ENCCs attenuated Brunner’s gland formation in organoid co-cultures [61] . Consistent with our observations, ENCCs and their progeny carry the potential to direct epithelial differentiation in favor of an endocrine phenotype, and these events are strongly influenced by Shh-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

Duan

Sawyer

Sontz

et al. 2022

Preprint

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BACKGROUND & AIMS: Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive model systems that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a role for enteric glia in neuroendocrine cell specification. Here we investigated the hypothesis that loss of menin in glial cells stimulated neuroendocrine differentiation and tumorigenesis. METHODS: Using Cre-lox technology, we generated a conditional glial fibrillary acidic protein-directed Men1 knockout (GFAPΔMen1) mouse model. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. siRNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel. RESULTS: GFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Mechanistically, Men1 deletion induced reprogramming from a mature glial phenotype toward a neuroendocrine lineage. Furthermore, blockade of Hedgehog signaling in enteric glia attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. CONCLUSIONS: GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.

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“…Dorsal root ganglion Neurons Moderate Rat; mouse (Islam et al, 2020;Pan et al, 2023) Intralingual ganglion Neurons Abundant distribution Mouse (Islam et al, 2023) Lingual root ganglion Neurons Abundant distribution Mouse (Islam et al, 2023) Submucosal nerve plexus Neurons High Rat; mouse (Tarif et al, 2023) Myenteric nerve plexus Neurons High Rat; mouse (Tarif et al, 2021) Abdominal sympathetic ganglia Neurons Extremely low Mouse (Dragatsis et al, 2000) Intestinal neurons Neurons Extremely low Mouse (Dragatsis et al, 2000) The gastrointestinal tract is an important part of the endocrine system. A study of rat pyloric glands revealed that HAP1 is specifically expressed in gastrin (G) cells (Yanai et al, 2020), which are neuroendocrine cells responsible for gastrin synthesis and secretion (Schubert, 2016), suggesting the possible involvement of HAP1 in the regulation of gastrin secretion. Enterochromaffin (EC) cells, which are the most abundant of all enteroendocrine cells, synthesize and secrete 95% of the 5-hydroxytryptamine (5-HT) (Rezzani et al, 2022).…”

Section: Location Tissues or Cells Expression Level Resourcesmentioning

confidence: 99%

Research advances in huntingtin-associated protein 1 and its application prospects in diseases

Wu,

Wang,

et al. 2024

Front. Neurosci.

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Huntingtin-associated protein 1 (HAP1) was the first protein discovered to interact with huntingtin. Besides brain, HAP1 is also expressed in the spinal cord, dorsal root ganglion, endocrine, and digestive systems. HAP1 has diverse functions involving in vesicular transport, receptor recycling, gene transcription, and signal transduction. HAP1 is strongly linked to several neurological diseases, including Huntington’s disease, Alzheimer’s disease, epilepsy, ischemic stroke, and depression. In addition, HAP1 has been proved to participate in cancers and diabetes mellitus. This article provides an overview of HAP1 regarding the tissue distribution, cell localization, functions, and offers fresh perspectives to investigate its role in diseases.

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Immunohistochemical relationships of huntingtin-associated protein 1 with enteroendocrine cells in the pyloric mucosa of the rat stomach

Cited by 9 publications

References 47 publications

Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours

Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours

GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

Research advances in huntingtin-associated protein 1 and its application prospects in diseases

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