# Broadening horizons: new links between cilia and heart development and disease **Authors:** Wenqi Ma, Zhuofeng Zhang, Yun Ma, Chengxu Ma PMC · DOI: 10.3389/fcvm.2026.1699088 · Frontiers in Cardiovascular Medicine · 2026-02-17 ## TL;DR This review explores how cilia defects during development can lead to heart defects and congenital heart disease. ## Contribution The paper unifies multiple molecular pathways into a 'cilia-LRO-heart' network to explain heart development and disease. ## Key findings - Defects in genes like CFAP45, ZIC3, and FOXJ1 disrupt cilia function, leading to heart malformations. - Ciliary dysfunction interrupts calcium signaling and Nodal-Pitx2 pathways, causing cardiac looping defects. - The study links cilia to valve diseases and fibrosis, offering new targets for diagnosis and treatment. ## Abstract Congenital heart disease (CHD) is the most common birth defect, and its pathogenesis is closely related to the abnormal establishment of the left-right (LR) body axis, which highly depends on the ciliary function of the left-right organizer (LRO). This review systematically expounds the molecular pathways by which ciliary structural and functional abnormalities cause cardiac malformations by integrating multi-species model evidence. We believe that defects in multiple conserved genes (including CFAP45, ZIC3, FOXJ1, NEK3, APLNR, and microRNAs) disrupt ciliary assembly, motility, or signaling capacity, leading to the disappearance of the leftward nodal flow or mechanical sensing failure within the LRO. This further interrupts the left-specific calcium ion flicker and the activation of the Nodal-Pitx2 signaling cascade, ultimately resulting in failed cardiac looping and structural defects (such as ventricular septal defect and transposition of the great arteries). This review integrates transcriptional regulation, protein stability, miRNA-mediated fine regulation, and the planar cell polarity (PCP) pathway into a unified “cilia-LRO-heart” network and explores the molecular mechanisms of cilia in valve diseases and cardiac fibrosis. This not only deepens the understanding of the fundamental biological processes of heart development but also provides new molecular targets and theoretical frameworks for the genetic diagnosis and counseling of related congenital heart diseases. ## Linked entities - **Genes:** CFAP45 (cilia and flagella associated protein 45) [NCBI Gene 25790], ZIC3 (Zic family zinc finger 3) [NCBI Gene 7547], FOXJ1 (forkhead box J1) [NCBI Gene 2302], NEK3 (NIMA related kinase 3) [NCBI Gene 4752], APLNR (apelin receptor) [NCBI Gene 187] - **Diseases:** congenital heart disease (MONDO:0005453), ventricular septal defect (MONDO:0002070), transposition of the great arteries (MONDO:0000153) ## Full-text entities - **Genes:** Lef1 (lymphoid enhancer binding factor 1) [NCBI Gene 16842] {aka 3000002B05, Lef-1}, Ptch1 (patched 1) [NCBI Gene 19206] {aka A230106A15Rik, Ptc, Ptc1, Ptch, mes, wig}, Ift88 (intraflagellar transport 88) [NCBI Gene 21821] {aka Tg737, Tg737Rpw, TgN737Rpw, Ttc10, flexo, fxo}, Hey1 (hairy/enhancer-of-split related with YRPW motif 1) [NCBI Gene 15213] {aka CHF2, HRT1, Herp2, Hesr1, bHLHb31, hesr-1}, SHH (sonic hedgehog signaling molecule) [NCBI Gene 6469] {aka HHG1, HLP3, HPE3, MCOPCB5, SMMCI, ShhNC}, MAPK9 (mitogen-activated protein kinase 9) [NCBI Gene 5601] {aka JNK-55, JNK2, JNK2A, JNK2ALPHA, JNK2B, JNK2BETA}, TMEM67 (transmembrane protein 67) [NCBI Gene 91147] {aka JBTS6, MECKELIN, MKS3, NPHP11, TNEM67}, GPR161 (G protein-coupled receptor 161) [NCBI Gene 23432] {aka RE2}, APLN (apelin) [NCBI Gene 8862] {aka APEL, XNPEP2}, SMAD4 (SMAD family member 4) [NCBI Gene 4089] {aka DPC4, JIP, MADH4, MYHRS}, DAAM1 (dishevelled associated activator of morphogenesis 1) [NCBI Gene 23002], DAND5 (DAN domain BMP antagonist family member 5) [NCBI Gene 199699] {aka CER2, CERL2, CKTSF1B3, COCO, CRL2, DANTE}, MYL2 (myosin light chain 2) [NCBI Gene 4633] {aka CMH10, MFM12, MLC-2, MLC-2s/v, MLC-2v, MLC2}, ndr1 (nodal-related 1) [NCBI Gene 799352] {aka CHUNP6892, NDR2, Ndr-1, Znr-2, sqt, znr2}, BMP5 (bone morphogenetic protein 5) [NCBI Gene 653], Gli (Gliotactin) [NCBI Gene 34927] {aka BG:DS09217.3, CG3903, Dmel\CG3903, l(2)35Dg, l(2)br45, n(2)k09033}, NUP93 (nucleoporin 93) [NCBI Gene 9688] {aka NIC96}, HNF4A (hepatocyte nuclear factor 4 alpha) [NCBI Gene 3172] {aka FRTS4, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha}, GJA1 (gap junction protein alpha 1) [NCBI Gene 2697] {aka AVSD3, CMDR, CX43, EKVP, EKVP3, GJAL}, Axin2 (axin 2) [NCBI Gene 12006] {aka Axi1, Axil, Conductin}, PITX2 (paired like homeodomain 2) [NCBI Gene 5308] {aka ARP1, ASGD4, Brx1, IDG2, IGDS, IGDS2}, smo (smoothened, frizzled class receptor) [NCBI Gene 30225] {aka CHUNP6862, smoh, smu, wu:fb70b01, wu:fc39h03}, SMAD3 (SMAD family member 3) [NCBI Gene 4088] {aka HSPC193, HsT17436, JV15-2, LDS1C, LDS3, MADH3}, DVL2 (dishevelled segment polarity protein 2) [NCBI Gene 1856], NEK8 (NIMA related kinase 8) [NCBI Gene 284086] {aka JCK, NEK12A, NPHP9, PKD8, RHPD2}, SIRT1 (sirtuin 1) [NCBI Gene 23411] {aka SIR2, SIR2L1, SIR2alpha}, IFT172 (intraflagellar transport 172) [NCBI Gene 26160] {aka BBS20, NPHP17, RP71, SLB, SRTD10, osm-1}, FOXJ1 (forkhead box J1) [NCBI Gene 2302] {aka CILD43, FKHL13, HFH-4, HFH4}, APLNR (apelin receptor) [NCBI Gene 187] {aka AGTRL1, APJ, APJR, HG11}, NOTCH1 (notch receptor 1) [NCBI Gene 4851] {aka AOS5, AOVD1, TAN1, hN1}, PRCP (prolylcarboxypeptidase) [NCBI Gene 5547] {aka HUMPCP, PCP}, PTPRA (protein tyrosine phosphatase receptor type A) [NCBI Gene 5786] {aka HEPTP, HLPR, HPTPA, HPTPalpha, LRP, PTPA}, FOXH1 (forkhead box H1) [NCBI Gene 8928] {aka FAST-1, FAST1}, PAEP (progestagen associated endometrial protein) [NCBI Gene 5047] {aka GD, GdA, GdF, GdS, PAEG, PEP}, MFAP2 (microfibril associated protein 2) [NCBI Gene 4237] {aka MAGP, MAGP-1, MAGP1}, DZIP1 (DAZ interacting zinc finger protein 1) [NCBI Gene 22873] {aka DZIP, DZIPt1, MMVP3, MVP3, SPGF47}, CXCR6 (C-X-C motif chemokine receptor 6) [NCBI Gene 10663] {aka BONZO, CD186, CDw186, STRL33, TYMSTR}, ACTA1 (actin alpha 1, skeletal muscle) [NCBI Gene 58] {aka ACTA, ASMA, CFTD, CFTD1, CFTDM, CMYO2A}, GLI2 (GLI family zinc finger 2) [NCBI Gene 2736] {aka CJS, HPE9, PHS2, THP1, THP2}, megf8 (multiple EGF-like-domains 8) [NCBI Gene 791154] {aka fb77g03, si:dkey-108f8.4, wu:fb77g03, zgc:158741}, ZIC3 (Zic family zinc finger 3) [NCBI Gene 7547] {aka HTX, HTX1, VACTERLX, ZNF203}, ARL6 (ARF like GTPase 6) [NCBI Gene 84100] {aka BBS3, RP55}, VANGL2 (VANGL planar cell polarity protein 2) [NCBI Gene 57216] {aka LPP1, LTAP, STB1, STBM, STBM1}, MCAM (melanoma cell adhesion molecule) [NCBI Gene 4162] {aka CD146, HEMCAM, METCAM, MUC18, MelCAM}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, NEK3 (NIMA related kinase 3) [NCBI Gene 4752] {aka HSPK36}, Hira (hira) [NCBI Gene 31680] {aka CG12153, Dhh, Dmel\CG12153, dHira, dhira, ssm}, Hes1 (hes family bHLH transcription factor 1) [NCBI Gene 15205] {aka Hry, bHLHb39}, Yif1b (Yip1 interacting factor homolog B (S. cerevisiae)) [NCBI Gene 77254] {aka 9430029K10Rik, Yip1b}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], BMP1 (bone morphogenetic protein 1) [NCBI Gene 649] {aka OI13, PCOLC, PCP, TLD}, ptc (patched) [NCBI Gene 35851] {aka BcDNA:RH36596, CG2411, Conf, Dmel\CG2411, Patched, Ptc_Dm}, cep104 (centrosomal protein 104) [NCBI Gene 560451] {aka si:ch211-147a11.5}, NEK11 (NIMA related kinase 11) [NCBI Gene 79858], BMP2 (bone morphogenetic protein 2) [NCBI Gene 650] {aka BDA2, BMP2A, SSFSC, SSFSC1}, NUP155 (nucleoporin 155) [NCBI Gene 9631] {aka ATFB15, N155}, Maml1 (mastermind like transcriptional coactivator 1) [NCBI Gene 103806] {aka D930008C07Rik, Mam-1, Mam1, mKIAA0200}, cfap74 (cilia and flagella associated protein 74) [NCBI Gene 335386] {aka fj08c09, si:dkeyp-87a12.1, wu:fj08c09}, BBS4 (Bardet-Biedl syndrome 4) [NCBI Gene 585] - **Diseases:** developmental malformations (MESH:C564254), Bardet Biedl syndrome (MESH:D020788), genetic defect (MESH:D030342), hydrocephalus (MESH:D006849), neural tube defects (MESH:D009436), cardiovascular abnormalities (MESH:D018376), endodermal defects (MESH:D018240), transposition (MESH:C536650), Atrial ventricular septal defect (MESH:D006345), heterotaxic cardiac development (MESH:D002658), pulmonary stenosis (MESH:D011666), mitral valve (MESH:D008944), truncus arteriosus (MESH:D014339), calcification of the aortic valve (MESH:C562942), OFT (MESH:D000092243), cranial neurodevelopmental defects (MESH:D003389), BAV (MESH:D000082862), HTX (MESH:D059446), bicuspid aortic valve (MESH:D000082882), ciliopathies (MESH:D000072661), shortened (MESH:C535850), ciliary abnormalities (MESH:D002925), structural and functional abnormalities (MESH:C566527), anomalous OFTs (MESH:D003784), ciliary degeneration (MESH:D009410), absence of spleen (MESH:D013160), calcific aortic stenosis (OMIM:109730), dextrocardia (MESH:D003914), primary cilia defects (MESH:C536287), ring abnormalities (MESH:D012303), infarction (MESH:D007238), heart failure (MESH:D006333), arrhythmias (MESH:D001145), structural (MESH:D020914), cardiac misalignment (MESH:D017760), cardiac asymmetries (MESH:D005146), organ malformations (MESH:D000092124), Bileaflet aortic valve (MESH:D001024), microtubule malformation (MESH:C567137), COPD (MESH:D029424), mitral-aortic valve disease (MESH:D008946), myocardial injury (MESH:D009202), heart valve insufficiency (MESH:D001022), univentricular pulmonary artery atresia (MESH:D018633), cardiac remodelling (MESH:D020257), Mks1 (MESH:C536133), coronary artery disease (MESH:D003324), cardiac dysfunction (MESH:D006331), sudden cardiac death (MESH:D016757), elongation failure (MESH:D051437), MI (MESH:D009203), mucinous tumour degeneration (MESH:D018297), deficiency of the IFT complex (MESH:C536778), mucinous (MESH:D002288), cardiovascular disease (MESH:D002318), CDON deficiency (MESH:D004314), valve diseases (MESH:D006349), atrial fibrillation (MESH:D001281), SS (MESH:D002278), cancers (MESH:D009369) - **Chemicals:** Fe2O3 (MESH:C000499), resveratrol (MESH:D000077185), calcium (MESH:D002118), hyaluronic acid (MESH:D006820), isoproterenol (MESH:D007545), adenine nucleotide (MESH:D000227), lipid (MESH:D008055), PTU (MESH:D011441), ADP (MESH:D000244), Ca2+ (-), DOX (MESH:D004317), glycosaminoglycan (MESH:D006025), oxygen (MESH:D010100) - **Species:** Drosophila melanogaster (fruit fly, species) [taxon 7227], Xenopus laevis (African clawed frog, species) [taxon 8355], Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Danio rerio (leopard danio, species) [taxon 7955] - **Mutations:** Thr1044Met, Pro1610Arg, serine/threonine ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12953466/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12953466/full.md ## References 274 references — full list in the complete paper: https://tomesphere.com/paper/PMC12953466/full.md --- Source: https://tomesphere.com/paper/PMC12953466