Hedgehog: functions and mechanisms

Varjosalo, Markku; Taipale, Jussi

doi:10.1101/gad.1693608

Cited by 1,121 publications

(1,065 citation statements)

References 269 publications

(282 reference statements)

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“…Here, we report up-regulation of genes involved in the Wnt and Hh signaling pathways in mammary epithelial cells isolated from heterotypic tissue recombinants. Activation of Wnt and/or Hh signaling are known to be involved in SC differentiation and cell fate determination of multiple tissues [43,44]. Our data show that Wnt and Hh downstream targets genes were upregulated in mammary epithelial cells by a prostatic stroma, particularly Ccnd1 (expression of protein product Cyclin D1 confirmed by immunolocalization), suggesting that prostatic stroma induced proliferation of mammary epithelium, as well as altering differentiation and cell fate, irrespective of their stage of lineage commitment or differentiation.…”

Section: Discussionmentioning

confidence: 61%

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

et al. 2009

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During development, cell differentiation is accompanied by the progressive loss of pluripotent gene expression and developmental potential, although de‐differentiation in specialized cells can be induced by reprogramming strategies, indicating that transdifferentiation potential is retained in adult cells. The stromal niche provides differentiating cues to epithelial stem cells (SCs), but current evidence is restricted to tissue types within the same developmental germ layer lineage. Anticipating the use of adult SCs for tissue regeneration, we examined if stroma can enforce lineage commitment across germ layer boundaries and promote transdifferentiation of adult epithelial SCs. Here, we report tissue‐specific mesenchyme instructing epithelial cells from a different germ layer origin to express dual phenotypes. Prostatic stroma induced mammary epithelia (or enriched Lin−CD29HICD24+/MOD mammary SCs) to generate glandular epithelia expressing both prostatic and mammary markers such as steroid hormone receptors and transcription factors including Foxa1, Nkx3.1, and GATA‐3. Array data implicated Hh and Wnt pathways in mediating stromal‐epithelial interactions (validated by increased Cyclin D1 expression). Other recombinants of prostatic mesenchyme and skin epithelia, or preputial gland mesenchyme and bladder or esophageal epithelia, showed foci expressing new markers adjacent to the original epithelial differentiation (e.g., sebaceous cells within bladder urothelium), confirming altered lineage specification induced by stroma and evidence of cross‐germ layer transdifferentiation. Thus, stromal cell niche is critical in maintaining (or redirecting) differentiation in adult epithelia. In order to use adult epithelial SCs in regenerative medicine, we must additionally regulate their intrinsic properties to prevent (or enable) transdifferentiation in specified SC niches. STEM CELLS 2009;27:3032–3042

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Section: Discussionmentioning

confidence: 61%

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

et al. 2009

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“…18 There are three secreted Hh ligand family member proteins: Sonic Hh (Shh), Indian Hh and desert Hh. 25,26 Hh signaling depends on the balance between activator and repressor forms of the glioma-associated oncogene family (Gli) of zincfinger transcription factors. The basic signaling pathway involves a 12-transmembrane domain receptor protein Patched 1 (Ptc1), the 7-transmembrane domain protein Smoothened (Smo), the suppressor of fused protein (Sufu) and the Gli transcription factors.…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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“…The high susceptibility to ERMS at E9.5, the decreased susceptibility at E11.5 and lack of Time of initiation of embryonal rhabdomyosarcoma F Nitzki et al susceptibility at E13.5 in our model nicely fits into this frame. Mesodermal cells that are ready to respond to Hh signaling to form muscle cells at E9.5 have probably adopted a different fate at E11.5 rendering them unresponsive to Hh-induced myogenesis (Varjosalo and Taipale, 2008). Hence, it becomes more and more difficult to induce ERMS at later stages.…”

Section: Discussionmentioning

confidence: 99%

Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice

et al. 2011

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Embryonal rhabdomyosarcoma (ERMS) is a tumor of the skeletal muscle in children and is frequently initiated by heterozygous germline mutations in the Hedgehog (Hh) receptor Patched1 (Ptch), both in humans and mice. Using a conditional knock-out strategy in Ptch flox/ þ mice, we demonstrate that early embryonic stages are more susceptible to ERMS development than later stages and that cells normally not committed to undergo myogenesis at this stage represent the major source of ERMS. We found that deletion of a single copy of the Ptch allele at E9.5 using the ubiquitously active Rosa26CreERT2 resulted in a tumor incidence of 88% but reached only 44% and 12% when the Ptch allele was inactivated at E11.5 and E13.5, respectively. Induction of the Ptch mutation at E9.5 did also significantly shorten ERMS-free survival and increased tumor multiplicity compared with tumor induction at E11.5 and E13.5. Interestingly, we observed a more that 10-fold reduction of ERMS incidence when the Ptch mutation was specifically introduced in Myf5-expressing cells, which is the myogenic factor expressed in all muscle cells at E9.5. We conclude that Myf5-negative cells are more susceptible to ERMS development than Myf5-positive embryonic precursors. As the propensity to undergo tumorigenic transformation declined with age, concomitant with the increase of stably committed muscle cells, it seems likely that the Ptch mutation favors tumor formation in progenitor cells, which have not yet acquired a muscle cell fate.

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Hedgehog: functions and mechanisms

Cited by 1,121 publications

References 269 publications

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

Autophagy and regulation of cilia function and assembly

Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice

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