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An SRRM3 regulated neural alternative splicing program is subverted to promote tumour progression in pancreatic neuroendocrine cells.

ABSTRACT: Pancreatic neuroendocrine tumours (PanNETs) are a heterogeneous group of neoplasms arising in pancreatic islets and altering the hormone secreting function of neuroendocrine cells. Genome wide approaches have revealed the genomic landscape of PanNETs but have not explained their problematic hormone secretion. We show here that alternative splicing (AS) deregulation is responsible for changes in the secretory ability of PanNET cells. We reveal that the RNA binding protein SRRM3 is upregulated in PanNETs and favours the inclusion of a group of alternative microexons in certain mRNAs. These microexons are part of a larger neural program regulated by SRRM3 and their inclusion results in protein isoforms that change stimulus-induced insulin trafficking and secretion. By downregulating SRRM3 or inhibiting its binding on three of the microexon bearing pre-mRNAs, in animal and cellular PanNET models, we prove the necessity of SRRM3 for hormone secretion, PanNET progression and the enhanced neural component of PanNET tumours.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Pancreatic Endocrine Carcinoma

SUBMITTER: Martina Samiotaki

LAB HEAD: Panagiota Kafasla

PROVIDER: PXD065389 | Pride | 2025-08-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	KEY_SRRM3.xlsx	Xlsx
	Kafasla_40530.7z	Other
	Kafasla_40530.pg_matrix.tsv	Tabular
	Kafasla_40530.unique_genes_matrix.tsv	Tabular

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Project description:Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling and in vivo optogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neurons in vivo using continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.

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An SRRM3 regulated neural alternative splicing program is subverted to promote tumour progression in pancreatic neuroendocrine cells.

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