INPP5E and Coordination of Signaling Networks in Cilia

Zhang, Renshuai; Tang, J. M.; Li, Tianliang; Zhou, Jun; Pan, Wei

doi:10.3389/fmolb.2022.885592

Cited by 10 publications

(9 citation statements)

References 56 publications

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“…2d ). It is likely that this reduction is due to loss of INPP5E and its broader role in maintaining cilia stability independently of AURKA’s actions 41 . Similar analysis of Pkd1 ∆/∆ kidneys found no changes in cilia structure (Fig.…”

Section: Resultsmentioning

confidence: 99%

Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice

Tham,

Cottle,

Zylberberg

et al. 2024

Nat Commun

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Aurora Kinase A (AURKA) promotes cell proliferation and is overexpressed in different types of polycystic kidney disease (PKD). To understand AURKA’s role in regulating renal cyst development we conditionally deleted the gene in mouse models of Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polyphosphate-5-phosphatase E (Inpp5e) mutations respectively. We show that while Aurka is dispensable for collecting duct development and homeostasis, its deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in cyst prevention and we show that (i) AURKA and AKT physically interact, (ii) AURKA regulates AKT activity in a kinase-independent manner and (iii) inhibition of AKT can reduce disease severity. AKT activation also regulates Aurka expression, creating a feed-forward loop driving renal cystogenesis. We find that the AURKA kinase inhibitor Alisertib stabilises the AURKA protein, agonizing its cystogenic functions. These studies identify AURKA as a master regulator of renal cyst development in different types of PKD, functioning in-part via AKT.

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Section: Resultsmentioning

confidence: 99%

Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice

Tham,

Cottle,

Zylberberg

et al. 2024

Nat Commun

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show abstract

“…Dysfunction of the module causes shorter ciliary lengths, attenuated Shh/tubulin signaling, and increased ciliary resorption with overall normal ciliation rates (Latour et al., 2020). The proteins CEP120 (Tsai et al., 2019) , KIAA0586 (Stephen et al., 2015) , C2CD3 (Tsai et al., 2019) , OFD1 (Thauvin‐Robinet et al., 2014) , KATNIP (Sanders et al., 2015) , INPP5E (Zhang et al., 2022) , PIBF1 (Kodani et al., 2015) , CPLANE1 (Toriyama et al., 2016) , CEP41 (Ki et al., 2020), and TMEM138 (J.H. Lee et al., 2012) act as “ciliogenesis mediators” and are implicated in regulating initial steps of centriole duplication/maturation and cilia formation/elongation.…”

Section: Resultsmentioning

confidence: 99%

Phenotypic variability in Joubert syndrome is partially explained by ciliary pathophysiology

Owens,

Hopkin,

Martin

et al. 2023

Annals of Human Genetics

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Introduction: Joubert syndrome (JS) arises from defects of primary cilia resulting in potential malformations of the brain, kidneys, eyes, liver, and limbs. Several of the 35+ genes associated with JS have recognized genotype/phenotype correlations, but most genes have not had enough reported individuals to draw meaningful conclusions.Methods: A PubMed literature review identified 688 individuals with JS across 32 genes and 112 publications to bolster known genotype/phenotype relationships and identify new correlations.All included patients had the “molar tooth sign” and a confirmed genetic diagnosis. Individuals were categorized by age, ethnicity, sex and the presence of developmental disability/intellectual disability, hypotonia, abnormal eye movements, ataxia, visual impairment, renal impairment, polydactyly, and liver abnormalities.Results: Most genes demonstrated unique phenotypic profiles. Grouping proteins based on physiologic interactions established stronger phenotypic relationships that reflect known ciliary pathophysiology. Age‐stratified data demonstrated that end‐organ disease is progressive in JS. Most genes demonstrated a significant skew towards having variants with either residual protein function or no residual protein function.Conclusion: This cohort demonstrates that clinically meaningful genotype/phenotype relationships exist within most JS‐related genes and can be referenced to allow for more personalized clinical care.

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“…The majority, such as CC2D2A and CEP290, localise to the ciliary transition zone, a specialised domain controlling ciliary protein content (Szymanska and Johnson 2012). Other JBTS proteins localise to the basal body (TALPID3/KIAA0586 or TOGARAM1) or the ciliary membrane (INPP5E) (Latour et al 2020; Zhang et al 2022; Stephen et al 2015). It can be hypothesised that dysfunction of these different proteins would contribute to a shared downstream mechanism resulting in the highly specific MTS seen in JBTS patients, as opposed to other ciliary proteins whose dysfunction does not cause JBTS.…”

Section: Introductionmentioning

confidence: 99%

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

Noble,

Masek,

Hofmann

et al. 2024

Preprint

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Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. In order to identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510 and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain, however do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation.

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INPP5E and Coordination of Signaling Networks in Cilia

Cited by 10 publications

References 56 publications

Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice

Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice

Phenotypic variability in Joubert syndrome is partially explained by ciliary pathophysiology

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

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