Biology subjects

Seika, P.

Publications and source records attributed to Seika, P..

3 recordsLinked to original sources

bioRxiv2026

Enteric neurons modulate colorectal cancer cell cycle through a PCSK1 - Methionine-Enkephalin Axis

Background and AimsThe tumor microenvironment in colorectal cancer (CRC) is richly innervated, yet the contribution of the enteric nervous system (ENS) to CRC biology remains poorly defined. ENS neurons express proenkephalin (PENK), which can be processed by proprotein convertase 1/3 (PCSK1) to generate Methionine-enkephalin (M-ENK), a bioactive peptide with growth-regulatory potential. We hypothesized that an ENS-derived PCSK1-M-ENK axis restrains CRC proliferation through opioid growth factor receptor (OGFr) signaling and is modulated by stress-associated glucocorticoid receptor (GR) signaling and GLP1 receptor (GLP1R) activity. MethodsPublicly available human CRC single-cell RNA-sequencing datasets were analyzed for OGFr expression. PCSK1 and M-ENK expression in murine ENS and tumor-associated tissue was assessed by immunofluorescence. Functional studies were performed using murine CRC organoids, and primary murine ENS neurons in mono- and co-culture. CRC proliferation was quantified by EdU incorporation following treatment with recombinant M-ENK, recombinant PCSK1, OGFr synthetic ligand naloxone, or PCSK1 inhibitors. Effects of dexamethasone and liraglutide on PCSK1 expression in ENS-containing murine tissue were evaluated. ResultsOGFr was enriched in CRC cells and positively associated with KRAS gene expression. A subset of adult murine colonic myenteric neurons expressed PCSK1 and M-ENK. M-ENK dose-dependently suppressed proliferation of CRC organoid cells. ENS neurons also suppressed CRC proliferation in a PCSK1-dependent manner. Dexamethasone reduced, whereas liraglutide increased, PCSK1 expression. ConclusionsThese findings define a previously unrecognized ENS-derived neuro-oncologic pathway that is associated with reduced CRC cell proliferation and identify the GR/GLP1R-PCSK1-M-ENK axis as a potentially actionable therapeutic node. SummaryThis study identifies a neuronal PCSK1 - M-ENK pathway in the ENS that directly suppresses colorectal cancer growth through local OGFr activation, revealing a previously unrecognized neuropeptidergic mechanism of tumor control within the intestinal microenvironment.

cancer biology↗

bioRxiv2026

Loss of enteric BDNF TrkB signaling and VIPergic dysfunction underlie gastrointestinal dysmotility in a Mecp2-null mouse model of Rett syndrome

Gastrointestinal (GI) dysmotility is a highly prevalent and clinically significant feature of Rett syndrome (RTT), yet its underlying mechanisms remain poorly defined. Here, we investigated these mechanisms of GI dysmotility in a Mecp2-null mouse model of RTT. First, we observed that MeCP2 was expressed in murine myenteric ganglia, including in enteric neurons and that Mecp2-null males developed maturation-associated functional regression in their GI motility. In dysmotile mice, longitudinal muscle-myenteric plexus tissue showed marked reductions in enteric Bdnf isoforms IV, VI, and II, whereas expression of the BDNF receptor isoforms TrkB.FL and TrkB.T1 was not significantly altered, consistent with reduced enteric BDNF-TrkB signaling. Despite impaired GI motility, Mecp2-null mice showed no significant changes in total enteric neuronal density, nitrergic neuronal abundance, or expression of Nos1, Chat, and Uchl1. In contrast, Vip expression was significantly reduced, while expression of VIP receptor genes: Vipr1 and Vipr2 was increased, indicating disrupted VIPergic signaling. Integration with publicly available enteric single-cell/nucleus datasets and targeted qRT-PCR further suggested altered inhibitory neuronal subtype composition, with reduced Vip+ Cartpt+ signatures and increased Nfia expression, suggesting that MeCP2 loss differentially affects distinct inhibitory neuronal subpopulations. Finally, conditional loss of TrkB.FL in neural crest-derived cells reduced Vip expression without recapitulating the full Mecp2-null VIPergic phenotype, indicating that impaired BDNF-TrkB signaling contributes to, but does not completely explain, the GI dysmotility in this model of RTT. Together, these findings identify enteric BDNF-TrkB and VIPergic dysfunction as key mechanisms underlying GI dysmotility in RTT.

neuroscience↗

bioRxiv2024

Reduced enteric BDNF-TrkB signaling drives glucocorticoid-mediated GI dysmotility

Stress is a key contributor to gastrointestinal (GI) dysmotility, particularly in patients with disorders of gut-brain interactions (DGBI). Since GI motility is governed by the enteric nervous system (ENS), stress may act by altering ENS function. While stress activates glucocorticoid signaling via the hypothalamic-pituitary-adrenal axis, the impact of stress-mediated glucocorticoid signaling on ENS biology remains poorly understood. In the central nervous system, glucocorticoids reduce specific isoforms of brain-derived neurotrophic factor (BDNF), impairing signaling through its receptor, TrkB, and contributing to behavioral dysfunction. However, the identity of ENS-specific Bdnf isoforms, their glucocorticoid sensitivity, and the effect of enhanced TrkB signaling on GI motility in stressed animals has not been characterized. Here, using male and female mice, we show that >85% of post-natal ENS Bdnf transcripts are glucocorticoid-responsive isoforms. We also demonstrate that both BDNF and its receptor TrkB (Ntrk2) are expressed by enteric neurons. In male mice, stress and administration of dexamethasone--a synthetic glucocorticoid receptor (GR) agonist--cause GI dysmotility, which we demonstrate is associated with significantly reduced Bdnf transcripts in the longitudinal muscle - myenteric plexus (LM-MP) tissue in vivo. Dexamethasone exposure also represses Bdnf transcript and mature protein levels in LM-MP tissue in vitro. Notably, treatment with HIOC, a selective TrkB agonist, rescues GI transit defects in dexamethasone-treated animals. These findings identify BDNF-TrkB signaling as a key modulator of stress-induced ENS dysfunction and highlight TrkB as a promising therapeutic target for GI dysmotility in DGBI. Significance statementHow stress causes gastrointestinal (GI) dysmotility is not well understood. GI motility is regulated by the enteric nervous system (ENS), which is responsive to brain-derived neurotrophic factor (BDNF), which signals through its receptor tropomyosin related kinase B (TrkB). By altering glucocorticoid signaling, stress modulates brains BDNF levels to cause behavioral changes. However, if this pathway is similarly responsible for stresss effects on GI dysmotility is not well understood. Here, by identifying the nature of ENS-specific Bdnf isoforms, studying their response to stress and glucocorticoid signaling, and testing the effect of a TrkB agonist to improve gut motility in a model of glucocorticoid-driven dysmotility, we implicate altered BDNF-TrkB signaling as an important mechanism driving stress-associated dysmotility.

neuroscience↗