Roles for Hedgehog signaling in adult organ homeostasis and repair

Petrova, Ralitsa; Joyner, Alexandra L.

doi:10.1242/dev.083691

Cited by 348 publications

(302 citation statements)

References 171 publications

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“…HHIP inhibits the HH pathway, a critical lung developmental pathway, through preventing three ligands from binding to its receptor, protein patched homolog 1, and eventually activating Gli1 (29). However, age-related emphysema in Hhip +/− mice might depend on a noncanonical HH pathway given that the HH pathway was regarded as an antagonist of aging in Alzheimer's disease and diabetes (35) because of its critical roles in organ-specific stem cells (36,37). We would expect a slower aging process because of partial de-repression of the HH pathway in Hhip +/− mice (22), whereas we observed accelerated aging-associated emphysema and increased cellular senescence in Hhip +/− mice.…”

Section: Hhip Interacts With Gstp1 and Enhances Glutathione-conjugatingmentioning

confidence: 99%

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Lao

Jiang

Yun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip+/−), we observed increased lung compliance and spontaneous emphysema in Hhip+/− mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip+/− vs. Hhip+/+ mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip+/− mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip+/− mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip+/− mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.

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Section: Hhip Interacts With Gstp1 and Enhances Glutathione-conjugatingmentioning

confidence: 99%

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Lao

Jiang

Yun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Considering that the conserved Hh signaling pathway (Briscoe and Thérond, 2013) has been reported to regulate the testis stem cell in mammals (Bitgood et al, 1996;Makela et al, 2011;Petrova and Joyner, 2014;Yao et al, 2002) and that the biological functions of the SUMO pathway in embryogenesis are highly conserved from Drosophila to mammals (Flotho and Melchior, 2013), it is intriguing to test whether the SUMO pathway is also required for mammalian adult testis by targeting the Hh signaling pathway. Actually, Gli proteins, the homologs of Ci in mammals, can be SUMOylated, as reported by two groups (Cox et al, 2010;Han et al, 2012), further supporting a conserved modification of the conserved transcription factors.…”

Section: Sumo Conjugation Promotes CI Activity In Terms Of Cysc Prolimentioning

confidence: 99%

SUMO regulates somatic cyst stem cells maintenance and directly targets hedgehog pathway in adult Drosophila testis

Pan

Zhang

et al. 2016

Development

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SUMO (Small ubiquitin-related modifier) modification (SUMOylation) is a highly dynamic post-translational modification (PTM) that plays important roles in tissue development and disease progression. However, its function in adult stem cell maintenance is largely unknown. Here, we report the function of SUMOylation in somatic cyst stem cell (CySC) self-renewal in adult Drosophila testis. The SUMO pathway cell-autonomously regulates CySC maintenance. Reduction of SUMOylation promotes premature differentiation of CySCs and impedes the proliferation of CySCs, which leads to a reduction in the number of CySCs. Consistent with this, CySC clones carrying a mutation of the SUMO-conjugating enzyme are rapidly lost. Furthermore, inhibition of the SUMO pathway phenocopies disruption of the Hedgehog (Hh) pathway, and can block the proliferation of CySCs induced by Hh activation. Importantly, the SUMO pathway directly regulates the SUMOylation of Hh pathway transcription factor Cubitus interruptus (Ci), which is required for promoting CySC proliferation. Thus, we conclude that SUMO directly targets the Hh pathway and regulates CySC maintenance in adult Drosophila testis.

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“…The Hedgehog (Hh) signaling pathway is evolutionarily conserved and involved in a wide variety of processes during embryogenesis and adult tissue homeostasis (Jiang and Hui, 2008;Hui and Angers, 2011;Briscoe and Therond, 2013;Petrova and Joyner, 2014). One of the most important roles that Hh signaling plays during vertebrate early development is patterning of the neural tube.…”

Section: Introductionmentioning

confidence: 99%

“…The Hh family of proteins operates the pathway by relieving these inhibitory mechanisms, which ultimately converts Ci and Gli into transcriptional activators and induces expression of Hh target genes. Interfering with these Hh inhibitory mechanisms often has severe consequences, ranging from defective embryonic development to tumorigenesis (Huangfu and Anderson, 2006;Jia and Jiang, 2006;Jiang and Hui, 2008;Hui and Angers, 2011;Briscoe and Therond, 2013;Petrova and Joyner, 2014).…”

Section: Introductionmentioning

confidence: 99%

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

Jin¹,

Schwend²,

Fu³

et al. 2016

Journal of Cell Science

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Hedgehog (Hh) signaling is fundamentally important for development and adult tissue homeostasis. It is well established that in vertebrates Sufu directly binds and inhibits Gli proteins, the downstream mediators of Hh signaling. However, it is unclear how the inhibitory function of Sufu towards Gli is regulated. Here we report that the Rusc family of proteins, the biological functions of which are poorly understood, form a heterotrimeric complex with Sufu and Gli. Upon Hh signaling, Rusc is displaced from this complex, followed by dissociation of Gli from Sufu. In mammalian fibroblast cells, knockdown of Rusc2 potentiates Hh signaling by accelerating signaling-induced dissociation of the Sufu-Gli protein complexes. In Xenopus embryos, knockdown of Rusc1 or overexpression of a dominant-negative Rusc enhances Hh signaling during eye development, leading to severe eye defects. Our study thus uncovers a novel regulatory mechanism controlling the response of cells to Hh signaling in vertebrates.

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Roles for Hedgehog signaling in adult organ homeostasis and repair

Cited by 348 publications

References 171 publications

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Hhip haploinsufficiency sensitizes mice to age-related emphysema

SUMO regulates somatic cyst stem cells maintenance and directly targets hedgehog pathway in adult Drosophila testis

Members of the Rusc protein family interact with Sufu and inhibit vertebrate Hedgehog signaling

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