Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Hwang, Sun‐Hee; Somatilaka, Bandarigoda N.; White, Kevin A.; Mukhopadhyay, Sutapa

doi:10.7554/elife.67121

Cited by 24 publications

(36 citation statements)

References 116 publications

(218 reference statements)

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“…If this is the case, then the activation of GLI repression is dependent on the status of the cilia and GLI transcriptional repression may be dynamically regulated in different developmental contexts. Consistent with this notion, GPR161 has recently been shown to repress HH signaling by regulation of GLI-R processing, through both ciliary and extraciliary mechanisms in a tissuespecific manner 59 .…”

Section: Discussionmentioning

confidence: 75%

GLI transcriptional repression is inert prior to Hedgehog pathway activation

Lex

Zhou

et al. 2022

Nat Commun

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The Hedgehog (HH) pathway regulates a spectrum of developmental processes through the transcriptional mediation of GLI proteins. GLI repressors control tissue patterning by preventing sub-threshold activation of HH target genes, presumably even before HH induction, while lack of GLI repression activates most targets. Despite GLI repression being central to HH regulation, it is unknown when it first becomes established in HH-responsive tissues. Here, we investigate whether GLI3 prevents precocious gene expression during limb development. Contrary to current dogma, we find that GLI3 is inert prior to HH signaling. While GLI3 binds to most targets, loss of Gli3 does not increase target gene expression, enhancer acetylation or accessibility, as it does post-HH signaling. Furthermore, GLI repression is established independently of HH signaling, but after its onset. Collectively, these surprising results challenge current GLI pre-patterning models and demonstrate that GLI repression is not a default state for the HH pathway.

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Section: Discussionmentioning

confidence: 75%

GLI transcriptional repression is inert prior to Hedgehog pathway activation

Lex

Zhou

et al. 2022

Nat Commun

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“…Neural stem cell-specific deletion of Gpr161 in mice manifests forebrain phenotypes such as ventriculomegaly, periventricular nodular heterotopia and altered neocortical cytoarchitectonic structure ( Shimada et al, 2019 ), and cerebellar tumors such as Shh-subtype medulloblastoma ( Shimada et al, 2018 ). A nonciliary but cAMP signaling competent Gpr161 mutant allele is associated with craniofacial abnormalities ( Hwang et al, 2021 ). GPR161 genetic mutations in humans are also associated with an increased risk for NTDs ( Kim et al, 2019 ) and the pituitary stalk interruption syndrome ( Karaca et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development

et al. 2021

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Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural tube and the craniofacies. However, the lineage specific role of Gpr161 in later embryonic development has not been thoroughly investigated. We studied the Wnt1-Cre lineage specific role of Gpr161 during mouse embryonic development. We observed three major gross morphological phenotypes in Gpr161 cKO (Gpr161 f/f; Wnt1-Cre) fetuses; protrusive tectum defect, encephalocele, and craniofacial skeletal defect. The overall midbrain tissues were expanded and cell proliferation in ventricular zones of midbrain was increased in Gpr161 cKO fetuses, suggesting that protrusive tectal defects in Gpr161 cKO are secondary to the increased proliferation of midbrain neural progenitor cells. Shh signaling activity as well as upstream Wnt signaling activity were increased in midbrain tissues of Gpr161 cKO fetuses. RNA sequencing further suggested that genes in the Shh, Wnt, Fgf and Notch signaling pathways were differentially regulated in the midbrain of Gpr161 cKO fetuses. Finally, we determined that cranial neural crest derived craniofacial bone formation was significantly inhibited in Gpr161 cKO fetuses, which partly explains the development of encephalocele. Our results suggest that Gpr161 plays a distinct role in midbrain development and in the formation of the craniofacial skeleton during mouse embryogenesis.

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“…The complete lack of a TULP3 cargo using a conditional knockout strategy does not equate to Tulp3 cko that shows a selective loss of the corresponding TULP3 cargo from cilia alone without affecting the extraciliary pools. In certain cases, TULP3 cargoes that are selectively deficient in trafficking to cilia without affecting the functionality can be generated by mutating ciliary localizing signals targeted by TULP3 (e.g., for the GPCR cargo GPR161 ( Hwang et al, 2021 ) or by targeting sequences that affect ciliary localization by TULP3 independent mechanisms (e.g., the RVxP motif for the lipidated protein ARL13B ( Gigante et al, 2020 ), also a TULP3 cargo).…”

Section: Dissecting Tulp3 Cargoes As Potential Clci and Ccdca Signals...mentioning

confidence: 99%

Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis

Walker

Maranto

Palicharla

et al. 2022

Front. Mol. Biosci.

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Primary cilia play counterregulatory roles in cystogenesis—they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent studies of the tubby family protein, Tubby-like protein 3 (TULP3), have provided new insights into the cilia-localized mechanisms that determine cyst growth. TULP3 is a key adapter of the intraflagellar transport complex A (IFT-A) in the trafficking of multiple proteins specifically into the ciliary membrane. Loss of TULP3 results in the selective exclusion of its cargoes from cilia without affecting their extraciliary pools and without disrupting cilia or IFT-A complex integrity. Epistasis analyses have indicated that TULP3 inhibits cystogenesis independently of the polycystins during kidney development but promotes cystogenesis in adults when polycystins are lacking. In this review, we discuss the current model of the cilia-dependent cyst activation (CDCA) mechanism in autosomal dominant polycystic kidney disease (ADPKD) and consider the possible roles of ciliary and extraciliary polycystins in regulating CDCA. We then describe the limitations of this model in not fully accounting for how cilia single knockouts cause significant cystic changes either in the presence or absence of polycystins. Based on available data from TULP3/IFT-A-mediated differential regulation of cystogenesis in kidneys with deletion of polycystins either during development or in adulthood, we hypothesize the existence of cilia-localized components of CDCA (cCDCA) and cilia-localized cyst inhibition (CLCI) signals. We develop the criteria for cCDCA/CLCI signals and discuss potential TULP3 cargoes as possible cilia-localized components that determine cystogenesis in kidneys during development and in adult mice.

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Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Cited by 24 publications

References 116 publications

GLI transcriptional repression is inert prior to Hedgehog pathway activation

GLI transcriptional repression is inert prior to Hedgehog pathway activation

Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development

Cilia-Localized Counterregulatory Signals as Drivers of Renal Cystogenesis

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