bims-bicyki 2023-06-25 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2023–06–25
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

[Inositol 1,4,5-triphosphate receptor 3 promotes renal cyst development in autosomal dominant polycystic kidney disease].
DNAJB11 -Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice.
Management of a Suspected Renal Cyst Infection With Intracystic Hemorrhage in a Patient With Autosomal Dominant Polycystic Kidney Disease.
Feasibility of artificial intelligence-based decision supporting system in tolvaptan prescription for autosomal dominant polycystic kidney disease.
Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis.
Estimating Patient Survival and Risk of End-Stage Kidney Disease in Patients With Autosomal Dominant Polycystic Kidney Disease in Iran.
Immune checkpoint activity regulates polycystic kidney disease progression.
Current progress in artificial intelligence-assisted medical image analysis for chronic kidney disease: A literature review.
Simultaneous Effects of a Selective EP2 Agonist, Omidenepag, and a Rho-Associated Coiled-Coil Containing Protein Kinase Inhibitor, Ripasudil, on Human Orbital Fibroblasts.
Thirst intensity survey in ADPKD patients.
Inversin (NPHP2) and Vangl2 are required for normal zebrafish cloaca formation.
Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects.

Sheng Li Xue Bao. 2023 Jun 25. 75(3): 328-338

[Inositol 1,4,5-triphosphate receptor 3 promotes renal cyst development in autosomal dominant polycystic kidney disease].

Zhi-Wei Qiu, Ming Liu, Hong Zhou, Bao-Xue Yang.

The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3 (IP3R3) in renal cyst development in autosomal dominant polycystic kidney disease (ADPKD). 2-aminoethoxy-diphenyl borate (2-APB) and shRNA were used to suppress the expression of IP3R3. The effect of IP3R3 on cyst growth was investigated in Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney specific Pkd1 knockout (PKD) mouse model. The underlying mechanism of IP3R3 in promoting renal cyst development was investigated by Western blot and immunofluorescence staining. The results showed that the expression level of IP3R3 was significantly increased in the kidneys of PKD mice. Inhibiting IP3R3 by 2-APB or shRNA significantly retarded cyst expansion in MDCK cyst model and embryonic kidney cyst model. Western blot and immunofluorescence staining results showed that hyperactivated cAMP-PKA signaling pathway in the growth process of ADPKD cyst promoted the expression of IP3R3, which was accompanied by a subcellular redistribution process in which IP3R3 was translocated from endoplasmic reticulum to intercellular junction. The abnormal expression and subcellular localization of IP3R3 further promoted cyst epithelial cell proliferation by activating MAPK and mTOR signaling pathways and accelerating cell cycle. These results suggest that the expression and subcellular distribution of IP3R3 are involved in promoting renal cyst development, which implies IP3R3 as a potential therapeutic target of ADPKD.
J Am Soc Nephrol. 2023 Jun 19.

DNAJB11 -Kidney Disease Develops from Reduced Polycystin-1 Dosage but not Unfolded Protein Response in Mice.

Sounak Ghosh Roy, Zhigui Li, Zi Guo, Kelly Long, Sonja Rehrl, Xin Tian, Ke Dong, Whitney Besse.

BACKGROUND: Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo . DNAJB11 encodes an Hsp40 co-chaperone in the endoplasmic reticulum (ER): the site of maturation of the ADPKD polycystin-1 (PC1) protein, and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases.
METHODS: We used germline and conditional alleles to model Dnajb11 -kidney disease in mice. In complementary experiments we generated two novel Dnajb11-/- cell lines that allow assessment of Polycystin-1 (PC1) C-terminal fragment and its ratio to the immature full-length protein.
RESULTS: Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11-/- mice are live-born at below the expected Mendelian ratio and die at weaning age with cystic kidneys. Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mice show no evidence of UPR activation nor cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis.
CONCLUSIONS: DNAJB11 -kidney disease is on the spectrum of ADPKD phenotypes with a Polycystin-1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.

DOI: https://doi.org/10.1681/ASN.0000000000000164
Cureus. 2023 May;15(5): e39319

Management of a Suspected Renal Cyst Infection With Intracystic Hemorrhage in a Patient With Autosomal Dominant Polycystic Kidney Disease.

Whitnee Otto, J Seth Psomiadis, Brandon Kirshner.

  Renal cyst infections are a serious complication in patients with autosomal dominant polycystic kidney disease (ADPKD). Cyst infections are challenging to treat and have a high incidence of complications such as sepsis and death. No guideline or evidence-based strategy for diagnosis or treatment of cyst infection currently exists. This lack of standardized guidance leads to individualized medical decision-making for each individual case, despite the high risk of morbidity and mortality associated with the infection. This case describes a 33-year-old female with a past medical history of ADPKD that presented with hematuria, increased urinary frequency, and left flank pain. On computed tomography (CT) imaging, she was found to have a large intracystic hemorrhage with an associated hematoma formation. Laboratory evaluation was remarkable for leukocytosis with left shift but normal renal function. Urinalysis displayed hematuria and the presence of protein, but the culture resulted in no growth. In the presence of clinical signs of infection, she was suspected to have an infected renal cyst that did not have glomerular communication, given the bland urinalysis and negative urine culture. Her hemoglobin stabilized, and she did not require embolization or percutaneous drainage of the cyst. Intravenous levofloxacin was initiated, and the patient clinically improved with the normalization of leukocytosis. Blood cultures remained negative, and she was discharged to home with a course of oral levofloxacin with a resolution of symptoms.

Keywords:  autosomal-dominant polycystic kidney disease; complicated urinary tract infection; cyst infection; genetic renal diseases; hemorrhagic cyst; renal cyst

DOI:  https://doi.org/10.7759/cureus.39319
Investig Clin Urol. 2023 05;64(3): 255-264

Feasibility of artificial intelligence-based decision supporting system in tolvaptan prescription for autosomal dominant polycystic kidney disease.

Jung Hyun Shin, Ye Hyun Kim, Myung Kyu Lee, Hyun-Seok Min, Hyungjoo Cho, Hyunsuk Kim, Yong Chul Kim, Yong Seong Lee, Tae Young Shin.

   PURPOSE: Total kidney volume (TKV) measurement is crucial for selecting treatment candidates in autosomal dominant polycystic kidney disease (ADPKD). We developed and investigated the performance of fully-automated 3D-volumetry model and applied it to software as a service (SaaS) for clinical support on tolvaptan prescription in ADPKD patients.
MATERIALS AND METHODS: Computed tomography scans of ADPKD patients taken between January 2000 and June 2022 were acquired from seven institutions. The quality of the images was manually reviewed in advance. The acquired dataset was split into training, validation, and test datasets at a ratio of 8.5:1:0.5. Convolutional, neural network-based automatic segmentation model was trained to obtain 3D segment mask for TKV measurement. The algorithm consisted of three steps: data preprocessing, ADPKD area extraction, and post-processing. After performance validation with the Dice score, 3D-volumetry model was applied to SaaS which is based on Mayo imaging classification for ADPKD.
RESULTS: A total of 753 cases with 95,117 slices were included. The differences between the ground-truth ADPKD kidney mask and the predicted ADPKD kidney mask were negligible, with intersection over union >0.95. The post-process filter successfully removed false alarms. The test-set performance was homogeneously equal and the Dice score of the model was 0.971; after post-processing, it improved to 0.979. The SaaS calculated TKV from uploaded Digital Imaging and Communications in Medicine images and classified patients according to height-adjusted TKV for age.
CONCLUSIONS: Our artificial intelligence-3D volumetry model exhibited effective, feasible, and non-inferior performance compared with that of human experts and successfully predicted the rapid ADPKD progressor.

Keywords:  Artificial intelligence; Image processing, computer-assisted; Multidetector computed tomography; Polycystic kidney, autosomal dominant

DOI:  https://doi.org/10.4111/icu.20220411
BMC Nephrol. 2023 Jun 22. 24(1): 182

Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis.

Michael Lioudis, Xiaolei Zhou, Eric Davenport, Sasikiran Nunna, Holly B Krasa, Dorothee Oberdhan, Ancilla W Fernandes.

   BACKGROUND: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression.
METHODS: This was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods.
RESULTS: In the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001).
CONCLUSIONS: Although limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

Keywords:  Autosomal dominant polycystic kidney disease (ADPKD); Clinical trial; Glomerular filtration rate; Kidney volume; Tolvaptan; Treatment

DOI:  https://doi.org/10.1186/s12882-023-03247-6
Iran J Kidney Dis. 2023 May;17(3): 141-149

Estimating Patient Survival and Risk of End-Stage Kidney Disease in Patients With Autosomal Dominant Polycystic Kidney Disease in Iran.

Tahereh Malakoutian, Shahrokh Izadi, Parisa Honarpisheh, Seyed Morteza Bagheri, Negin Saffarzadeh, Hounaz Akbari.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disease that can affect several organs. The clinical course of the disease varies among patients; some never become symptomatic, and others reach end-stage kidney disease (ESKD) in the 5th decade of their life.
METHODS: This historical cohort study was conducted on ADPKD patients to investigate kidney and patient survival rates and related risk factors in Iran. Survival analysis and risk ratio calculation were performed using the Cox proportional hazards model, Kaplan- Meier method, and log-rank test.
RESULTS: Among the 145 participants, 67 developed ESKD, and 20 died before the end of the study period. Developing chronic kidney disease (CKD) at the age of ≤ 40, baseline serum creatinine level (SCr) of more than 1.5 mg/dL, and cardiovascular disease increased the risk of ESKD by 4, 1.8, and 2.4 times; respectively. Patient survival analysis revealed a fourfold increase in mortality if the glomerular filtration rate (GFR) declined more than 5 cc/min annually and if CKD was diagnosed at the age of ≤ 40. Vascular thrombotic events or ESKD in the course of disease increased the risk of death by approximately 6- and 7-fold, respectively. Kidney survival was 48% by the age of 60 and 28% by the age of 70. Patient survival was 86.05% at the age of 60 and 67.99% at the age of 70. Additionally, men had a significantly better renal function and survival than women.
CONCLUSION: Elevated baseline SCr and cardiovascular disease can increase ESKD risk in ADPKD patients. A rapid decline in GFR, ESKD development, and vascular thrombotic events increase the risk of death, but early CKD can affect both. DOI: 10.52547/ijkd.7551.
JCI Insight. 2023 06 22. pii: e161318. [Epub ahead of print]8(12):

Immune checkpoint activity regulates polycystic kidney disease progression.

Emily K Kleczko, Dustin T Nguyen, Kenneth H Marsh, Colin D Bauer, Amy S Li, Marie-Louise T Monaghan, Michael D Berger, Seth B Furgeson, Berenice Y Gitomer, Michel B Chonchol, Eric T Clambey, Kurt A Zimmerman, Raphael A Nemenoff, Katharina Hopp.

  Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8+ T cells and slow tumor growth. We have previously shown that in PKD, CD8+ T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti-PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti-PD-1 plus anti-CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8+ T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.

Keywords:  Adaptive immunity; Monogenic diseases; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.161318
Comput Struct Biotechnol J. 2023 ;21 3315-3326

Current progress in artificial intelligence-assisted medical image analysis for chronic kidney disease: A literature review.

Dan Zhao, Wei Wang, Tian Tang, Ying-Ying Zhang, Chen Yu.

  Chronic kidney disease (CKD) causes irreversible damage to kidney structure and function. Arising from various etiologies, risk factors for CKD include hypertension and diabetes. With a progressively increasing global prevalence, CKD is an important public health problem worldwide. Medical imaging has become an important diagnostic tool for CKD through the non-invasive identification of macroscopic renal structural abnormalities. Artificial intelligence (AI)-assisted medical imaging techniques aid clinicians in the analysis of characteristics that cannot be easily discriminated by the naked eye, providing valuable information for the identification and management of CKD. Recent studies have demonstrated the effectiveness of AI-assisted medical image analysis as a clinical support tool using radiomics- and deep learning-based AI algorithms for improving the early detection, pathological assessment, and prognostic evaluation of various forms of CKD, including autosomal dominant polycystic kidney disease. Herein, we provide an overview of the potential roles of AI-assisted medical image analysis for the diagnosis and management of CKD.

Keywords:  Artificial intelligence; Chronic kidney disease; Deep learning; Radiomics

DOI:  https://doi.org/10.1016/j.csbj.2023.05.029
J Ocul Pharmacol Ther. 2023 Jun 23.

Simultaneous Effects of a Selective EP2 Agonist, Omidenepag, and a Rho-Associated Coiled-Coil Containing Protein Kinase Inhibitor, Ripasudil, on Human Orbital Fibroblasts.

Fumihito Hikage, Megumi Watanabe, Tatsuya Sato, Araya Umetsu, Yuri Tsugeno, Masato Furuhashi, Hiroshi Ohguro.

  Purpose: To assess the combined effects of omidenepag (OMD), a selective EP2 agonist, and ripasudil (Rip), an inhibitor of rho-associated coiled-coil containing protein kinases, on the human orbital adipose tissue, two-dimensional (2D) or three-dimensional (3D) cultures of human orbital fibroblasts (HOFs) were employed. Methods: Cellular metabolic functions (2D), physical (3D), lipid staining (3D), and quantitative polymerase chain reaction for adipogenesis-related genes, PPARγ and AP2, and extracellular matrix (ECM) molecules, including collagen (COL)1, 4, and 6, and fibronectin (FN) (3D) were evaluated in the presence of OMD (100 nM) and/or Rip (10 μM). Results: Real-time metabolic analyses revealed that the adipogenic differentiation (DIF+) with OMD significantly shifted an energetic state toward energetic, whereas DIF+ with Rip significantly shifted that toward quiescent. In the case of both drugs upon DIF+, the metabolic effect of OMD was predominant. DIF+ induced enlargement and stiffed 3D spheroid with increased lipid staining and mRNA expression of adipogenesis-related genes, COL4 and COL6, and decreased the expression of COL1. In the presence of OMD and/or Rip to DIF+, (1) the sizes were further increased by Rip and the stiffness was significantly decreased by OMD or Rip and (2) COL4 or AP2 expression was substantially increased by OMD or Rip, respectively. Conclusion: The results presented herein indicate that the metabolic effects of OMD and Rip exerted opposing effects and the effects of OMD toward Ap2 and ECM expressions were distinct from those of Rip, but the effects of OMD toward the physical aspects and adipogenesis of the 3D cultured HOFs were similar to the effects of Rip.

Keywords:  3-dimension (3D) spheroid culture; Omidenepag (OMD); ROCK; Seahorse bioanalyzer; human orbital fibroblasts (HOFs); ripasudil (Rip)

DOI:  https://doi.org/10.1089/jop.2023.0025
Clin Exp Nephrol. 2023 Jun 23.

Thirst intensity survey in ADPKD patients.

Sibel Gokcay Gokcay Bek, Nuriye Yıldız, Mahmud Islam, Metin Ergul, Irem Sarıoglu, Dilek Guven Taymez, Necmi Eren, Hande Uslu, Mesude Tosun, Erkan Dervisoglu, Betul Kalender, Sibel Balcı, Nana Waldreus.

   INTRODUCTION: With increased fluid intake and tolvaptan treatment, the growth rate of cysts can be theoretically decelerated in autosomal polycystic kidney disease. In this prospective study, it was planned to evaluate thirst sensation in these patients and the parameters affecting its intensity.
METHODS: Forty-one ADPKD patients on tolvaptan and 40 ADPKD patients not on tolvaptan as the control group were evaluated for thirst distress sensation and intensity. The feeling of thirst and the discomfort caused by excessive fluid intake was assessed with Thirst Distress Scale-HF 12 questions (60/12). Thirst intensity was evaluated with a 100 mm visual scale.
RESULTS: Of the whole group, 35.8% (29) were males, and 64.2% (52) were females. The mean age of the tolvaptan group was 39.17 ± 9.35 years and for the control group, it was 41.95 ± 12.29 years. There was a negative correlation between the thirst distress score of the patients and an increase in creatinine level after a year of tolvaptan treatment (r = - 0.335, p = 0.035). The patients not taking thiazide had higher thirst intensity scores (p = 0.004). There was no impact of tolvaptan dosage, total kidney volume, serum sodium, urinary osmolarity or eGFR on thirst distress and thirst intensity scores.
DISCUSSION/CONCLUSION: Only thiazide co-treatment had a positive impact on thirst distress and intensity when given tolvaptan. Thirst Distress Scale for ADPKD patients can be used to classify patients before and during tolvaptan treatment.

Keywords:  ADPKD; Thirst sensation and intensity; Tolvaptan

DOI:  https://doi.org/10.1007/s10157-023-02373-7
Biochem Biophys Res Commun. 2023 Jun 19. pii: S0006-291X(23)00813-6. [Epub ahead of print]673 9-15

Inversin (NPHP2) and Vangl2 are required for normal zebrafish cloaca formation.

Hui Wang, Friedemann Zaiser, Priska Eckert, Johannes Ruf, Nicolas Kayser, Anna C Veenstra, Merle Müller, Rebecca Haas, Gerd Walz, Toma A Yakulov.

  Nephronophthisis (NPH), an autosomal recessive ciliopathy, results from mutations in more than 20 different genes (NPHPs). These gene products form protein complexes that regulate trafficking within the cilium, a microtubular structure that plays a crucial role in developmental processes. Several NPHPs, including NPHP2/Inversin, have been linked to extraciliary functions. In addition to defining a specific segment of primary cilia (Inversin compartment), NPHP2 participates in planar cell polarity (PCP) signaling along with Dishevelled and Vangl family members. We used the mutant zebrafish line invssa36157, containing a stop codon at amino acid 314, to characterize tissue-specific functions of zebrafish Nphp2. The invssa36157 line exhibits mild ciliopathy phenotypes and increased glomerular and cloaca cyst formation. These mutants showed enhanced susceptibility to the simultaneous depletion of the nphp1/nphp2/nphp8 module, known to be involved in the cytoskeletal organization of epithelial cells. Notably, simultaneous depletion of zebrafish nphp1 and vangl2 led to a pronounced increase in cloaca malformations in the invssa36157 mutant embryos. Time-lapse imaging showed that the pronephric cells correctly migrated towards the ectodermal cells in these embryos, but failed to form the cloaca opening. Despite these abnormal developments, cellular fate does not seem to be affected in nphp1 and vangl2 MO-depleted invssa36157 mutants, as shown by in situ hybridizations for markers of pronephros and ectodermal cell development. However, significantly reduced apoptotic activity was observed in this double knockdown model, signifying the role of apoptosis in cloacal morphogenesis. Our findings underscore the critical interplay of nphp1, nphp2/Inversin, and vangl2 in orchestrating normal cloaca formation in zebrafish, shedding light on the complex molecular mechanisms underlying ciliopathy-associated phenotypes.

Keywords:  Cell migration; Cloaca; Inversin; NPHP2; Nephronophthisis; Planar cell polarity; Vangl2; Zebrafish

DOI:  https://doi.org/10.1016/j.bbrc.2023.06.058
bioRxiv. 2023 Jun 07. pii: 2023.06.07.544132. [Epub ahead of print]

Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects.

Richard Francis, Jovenal T San Agustin, Heather L Szabo Rogers, Cheng Cui, Julie A Jonassen, Thibaut Eguether, John A Follit, Cecilia W Lo, Gregory J Pazour.

Ciliopathies are associated with wide spectrum of structural birth defects (SBD), indicating important roles for cilia in development. Here we provide novel insights into the temporospatial requirement for cilia in SBDs arising from deficiency in Ift140 , an intraflagellar transport protein regulating ciliogenesis. Ift140 deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula, randomized heart looping, congenital heart defects (CHD), lung hypoplasia, renal anomalies, and polydactyly. Tamoxifen inducible CAG-Cre deletion of a floxed Ift140 allele between E5.5 to 9.5 revealed early requirement for Ift140 in left-right heart looping regulation, mid to late requirement for cardiac outflow septation and alignment, and late requirement for craniofacial development and body wall closure. Surprisingly, CHD was not observed with four Cre drivers targeting different lineages essential for heart development, but craniofacial defects and omphalocele were observed with Wnt1-Cre targeting neural crest and Tbx18-Cre targeting epicardial lineage and rostral sclerotome through which trunk neural crest cells migrate. These findings revealed cell autonomous role of cilia in cranial/trunk neural crest mediated craniofacial and body wall closure defects, while non-cell autonomous multi-lineage interactions underlie CHD pathogenesis, revealing unexpected developmental complexity for CHD associated with ciliopathy.

DOI: https://doi.org/10.1101/2023.06.07.544132