Inhibition of Sonic hedgehog signaling in vivo results in craniofacial neural crest cell death

Ahlgren, Sara; Bronner‐Fraser, Marianne

doi:10.1016/s0960-9822(00)80052-4

Cited by 273 publications

(222 citation statements)

References 37 publications

Supporting

Mentioning

210

Contrasting

Unclassified

Order By: Relevance

“…Moreover, the cyclin-dependent kinase inhibitor p27, a promoter of cell-cycle arrest and differentiation, has been reported to also have a proapoptotic function (Wang et al, 1997; for review, see PhilippStaheli et al, 2001;Coqueret, 2003). A role for Shh signaling in controlling cell-death events has also been suggested by the widespread apoptosis observed in neural progenitors after inhibition of Shh activity (Ahlgren and Bronner-Fraser, 1999;Charrier et al, 2001) and by the ability of the Hedgehog receptor Patched to trigger apoptosis in the absence of Shh signal (Thibert et al, 2003). Whether REN-induced apoptosis is related to its ability to regulate both p27 and Hedgehog signaling needs to be investigated further.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog AntagonistREN^KCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors

Argenti¹,

Gallo²,

Marcotullio³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

During the early development of the cerebellum, a burst of granule cell progenitor (GCP) proliferation occurs in the outer external granule layer (EGL), which is sustained mainly by Purkinje cell-derived Sonic Hedgehog (Shh). Shh response is interrupted once GCPs move into the inner EGL, where granule progenitors withdraw proliferation and start differentiating and migrating toward the internal granule layer (IGL). Failure to interrupt Shh signals results in uncoordinated proliferation and differentiation of GCPs and eventually leads to malignancy (i.e., medulloblastoma). The Shh inhibitory mechanisms that are responsible for GCP growth arrest and differentiation remain unclear. Here we report that REN, a putative tumor suppressor frequently deleted in human medulloblastoma, is expressed to a higher extent in nonproliferating inner EGL and IGL granule cells than in highly proliferating outer EGL cells. Accordingly, upregulated REN expression occurs along GCP differentiation in vitro, and, in turn, REN overexpression promotes growth arrest and increases the proportion of p27/Kip1 ϩ GCPs. REN also impairs both Gli2-dependent gene transcription and Shh-enhanced expression of the target Gli1 mRNA, thus antagonizing the Shh-induced effects on the proliferation and differentiation of cultured GCPs. Conversely, REN functional knock-down impairs Hedgehog antagonism and differentiation and sustains the proliferation of GCPs. Finally, REN enhances caspase-3 activation and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling apoptotic GCP numbers; therefore, the pattern of REN expression, its activity, and its antagonism on the Hedgehog pathway suggest that this gene may represent a restraint of Shh signaling at the outer to inner EGL GCP transitions. Medulloblastoma-associated REN loss of function might withdraw such a limiting signal for immature cell expansion, thus favoring tumorigenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Hedgehog AntagonistREN^KCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors

Argenti¹,

Gallo²,

Marcotullio³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…There is increasing evidence that Hh signaling can regulate growth and survival in both differentiated and undifferentiated cells (47)(48)(49) and can also regulate lineage-specific differentiation (50)(51)(52). Hh family members tend to act in a paracrine fashion (12).…”

Section: Discussionmentioning

confidence: 99%

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

Niemann

Undén

Lyle

et al. 2003

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

174

140

View full text Add to dashboard Cite

In mammalian epidermis, the level of ␤-catenin signaling regulates lineage selection by stem cell progeny. High levels of ␤-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of ␤-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks ␤-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of ␤-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor, Patched (PTCH͞Ptch). In ⌬NLef1 tumors Ptch mRNA is up-regulated in the absence of SHH. We now show that PTCH is up-regulated in both human and mouse sebaceous tumors and is accompanied by overexpression of Indian hedgehog (IHH). In normal sebaceous glands IHH is expressed in differentiated sebocytes and the transcription factor GLI1 is activated in sebocyte progenitors, suggesting a paracrine signaling mechanism. PTCH1 and IHH are up-regulated during human sebocyte differentiation in vitro and inhibition of hedgehog signaling inhibits growth and stimulates differentiation. Overexpression of ⌬NLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between ␤-catenin and hedgehog signaling in the epidermis in which SHH promotes proliferation of progenitors of the hair lineages whereas IHH stimulates proliferation of sebocyte precursors.

show abstract

“…Whereas a targeted null mutation in Shh caused severe cranial deficiencies that initially precluded direct assessment of the role of Shh in facial morphogenesis (Chiang et al, 1996), inhibition of Shh signaling in the outgrowing chick frontonasal process with a function blocking antibody inhibited facial outgrowth and caused cleft lip (Hu and Helms, 1999). Ahlgren and Bronner-Fraser (1999) showed that inhibition of Shh in the cranial mesenchyme also caused neural crest mesenchymal cell death. Moreover, Ahlgren et al (2002) demonstrated that application of Shh protein rescued cranial mesenchymal death in chick embryos induced by ethanol treatment.…”

Section: The Shh Pathwaymentioning

confidence: 99%

Development of the upper lip: Morphogenetic and molecular mechanisms

Jiang

Bush

Lidral

2005

Developmental Dynamics

282

304

View full text Add to dashboard Cite

The vertebrate upper lip forms from initially freely projecting maxillary, medial nasal, and lateral nasal prominences at the rostral and lateral boundaries of the primitive oral cavity. These facial prominences arise during early embryogenesis from ventrally migrating neural crest cells in combination with the head ectoderm and mesoderm and undergo directed growth and expansion around the nasal pits to actively fuse with each other. Initial fusion is between lateral and medial nasal processes and is followed by fusion between maxillary and medial nasal processes. Fusion between these prominences involves active epithelial filopodial and adhering interactions as well as programmed cell death. Slight defects in growth and patterning of the facial mesenchyme or epithelial fusion result in cleft lip with or without cleft palate, the most common and disfiguring craniofacial birth defect. Recent studies of craniofacial development in animal models have identified components of several major signaling pathways, including Bmp, Fgf, Shh, and Wnt signaling, that are critical for proper midfacial morphogenesis and/or lip fusion. There is also accumulating evidence that these signaling pathways cross-regulate genetically as well as crosstalk intracellularly to control cell proliferation and tissue patterning. This review will summarize the current understanding of the basic morphogenetic processes and molecular mechanisms underlying upper lip development and discuss the complex interactions of the various signaling pathways and challenges for understanding cleft lip pathogenesis.

show abstract

Inhibition of Sonic hedgehog signaling in vivo results in craniofacial neural crest cell death

Cited by 273 publications

References 37 publications

Hedgehog AntagonistREN^KCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors

Hedgehog AntagonistREN^KCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

Development of the upper lip: Morphogenetic and molecular mechanisms

Contact Info

Product

Resources

About

Inhibition of Sonic hedgehog signaling in vivo results in craniofacial neural crest cell death

Cited by 273 publications

References 37 publications

Hedgehog AntagonistRENKCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors

Hedgehog AntagonistRENKCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

Development of the upper lip: Morphogenetic and molecular mechanisms

Contact Info

Product

Resources

About

Hedgehog AntagonistREN^KCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors

Hedgehog AntagonistREN^KCTD11Regulates Proliferation and Apoptosis of Developing Granule Cell Progenitors