Thomsen, O. K. | bioRxiv Science

bioRxiv2026

Distribution of the glucagon receptor in periventricular brain barrier interfaces including motile and primary cilia in rat brain

Glucagon is a key metabolic hormone regulating blood glucose and appetite, yet little is known about its actions within the brain. Here, we investigated its receptor (GCGR) localization in periventricular brain barrier interfaces in young rats using immunohistochemical and immunofluorescence approaches. GCGR was enriched in the proximal region of motile ependymal cilia lining the ventricles, as well as in tanycytic primary cilia and cytoplasmic extensions within the hypothalamus. Additional immunostaining was observed in ciliated cells of the subcommissural organ and, more heterogeneously, in choroid plexus epithelium and associated primary cilia, while other circumventricular organs lacked detectable GCGR. These findings identify brain cilia and tanycytes as previously unrecognized sites of glucagon receptor localization and suggest that glucagon signaling at brain barrier interfaces may contribute to integrating peripheral metabolic cues with central homeostatic circuits.

neuroscience↗

bioRxiv2024

TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development

Transforming Growth Factor-Beta-Activated Kinase 1 (TAK1/MAP3K7), along with its upstream regulators TAK1-Binding Protein 2 (TAB2) and the catalytic alpha-subunit of Protein Kinase A (PKA-C/PRKACA), has been identified as a pivotal player in regulation of developmental processes. Haploinsufficiency of TAB2 causes Congenital Heart Disease (CHD) and rare variants in PKA-C and TAK1 cause cardioacrofacial dysplasia (CAFD), and Frontometaphyseal Dysplasia (FMD) and cardiospondylocarpofacial syndrome (CSCFS), respectively, rare multisystem syndromes, where CHD may appear in the clinical spectrum. We hypothesized that TAK1 plays a significant role in heart development and CHD and addressed this by genetic analysis in CHD patient cohorts and experiments in cell and animal models. Exome sequencing data from 1,471 CHD patients with extracardiac anomalies (syndromic CHD, sCHD), 2,405 patients with nonsyndromic CHD (nsCHD) and 45,082 controls showed increased burden of rare TAB2 and TAK1 variants in sCHD, but not in nsCHD. Detailed characterization of tak1-/-and tab2-/- zebrafish mutants revealed cardiac defects (dilated atrium, trabeculation defects, tachycardia and reduced contractility) as well as extracardiac developmental anomalies. RNA sequencing of tak1-/- mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins. Experiments with cell cultures and analysis of zebrafish larvae and gastruloids indicated that TAK1 via TAB2 and PKA-C is activated at the primary cilium during cardiomyogenesis and that TAK1 activation at this site is enhanced by cardiomyogenic signaling molecules, including ligands of the TGFB/BMP superfamily. Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or administration of small molecule inhibitors targeting TAK1 inhibited ciliary signaling and cardiomyocyte differentiation in vitro, while FMD-causing mutations in TAK1 reduced its ciliary localization. In conclusion, our data establishes a central role for TAK1 and its upstream regulators in cardiac development and syndromic CHD, coordinated via the primary cilium.

developmental biology↗