Developmental Signals - Sonic hedgehog - Revision history

Z8600021 at 23:01, 1 December 2021

2021-12-01T23:01:03Z

← Older revision		Revision as of 10:01, 2 December 2021
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			* '''Controlling tissue patterning by translational regulation of signaling transcripts through the core translation factor eIF3c'''{{#pmid:34752747\|PMID34752747}} "Although gene expression is tightly regulated during embryonic development, the impact of translational control has received less experimental attention. Here, we find that eukaryotic translation initiation factor-3 (eIF3) is required for Shh-mediated tissue patterning. Analysis of loss-of-function eIF3 subunit c (Eif3c) mice reveal a unique sensitivity to the Shh receptor patched 1 (Ptch1) dosage. Genome-wide in vivo enhanced cross-linking immunoprecipitation sequence (eCLIP-seq) shows unexpected specificity for eIF3 binding to a pyrimidine-rich motif present in subsets of 5'-UTRs and a corresponding change in the translation of these transcripts by ribosome profiling in Eif3c loss-of-function embryos. We further find a transcript specific effect in Eif3c loss-of-function embryos whereby translation of Ptch1 through this pyrimidine-rich motif is specifically sensitive to eIF3 amount. Altogether, this work uncovers hidden specificity of housekeeping translation initiation machinery for the translation of key developmental signaling transcripts."

	* '''The neocortical progenitor specification program is established through combined modulation of SHH and FGF signaling'''{{#pmid:32737167\|PMID32737167}} "Low levels of {{FGF}}15 control progenitor proliferation and differentiation during neocortical development but little is known on how {{FGF}}15 expression is maintained. Our studies identified {{SHH}} signaling as a critical activator of FGF15 expression during corticogenesis. We found that Sufu, via Gli3R, ensured low levels of FGF15 was expressed to prevent abnormal specification of neocortical progenitors. These studies advance our knowledge on the molecular mechanisms guiding the generation of specific neocortical neuronal lineages, their implications in neurodevelopmental diseases, and may guide future studies on how progenitor cells may be utilized for brain repair."		* '''The neocortical progenitor specification program is established through combined modulation of SHH and FGF signaling'''{{#pmid:32737167\|PMID32737167}} "Low levels of {{FGF}}15 control progenitor proliferation and differentiation during neocortical development but little is known on how {{FGF}}15 expression is maintained. Our studies identified {{SHH}} signaling as a critical activator of FGF15 expression during corticogenesis. We found that Sufu, via Gli3R, ensured low levels of FGF15 was expressed to prevent abnormal specification of neocortical progenitors. These studies advance our knowledge on the molecular mechanisms guiding the generation of specific neocortical neuronal lineages, their implications in neurodevelopmental diseases, and may guide future studies on how progenitor cells may be utilized for brain repair."
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	* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} {{bone marrow}} stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}		* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} {{bone marrow}} stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}

	* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.
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			* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.

	* '''Region-specific endodermal signals direct {{neural crest}} cells to form the three {{middle ear}} ossicles'''{{#pmid:30630826\|PMID30630826}} "Defects in the middle ear ossicles - {{malleus}}, {{incus}} and {{stapes}} - can lead to conductive hearing loss. During development, {{neural crest}} cells (NCCs) migrate from the dorsal hindbrain to specific locations in {{pharyngeal arch}} (PA) 1 and 2, to form the malleus-incus and stapes, respectively. It is unclear how migratory NCCs reach their proper destination in the PA and initiate mesenchymal condensation to form specific ossicles. We show that secreted molecules sonic hedgehog ({{SHH}}) and bone morphogenetic protein 4 ({{BMP}}4) emanating from the pharyngeal {{endoderm}} are important in instructing region-specific NCC condensation to form malleus-incus and stapes, respectively, in mouse. Tissue-specific knockout of {{Shh}} in the pharyngeal endoderm or Smo (a transducer of SHH signaling) in NCCs causes the loss of malleus-incus condensation in PA1 but only affects the maintenance of stapes condensation in PA2. By contrast, knockout of {{Bmp}}4 in the pharyngeal endoderm or Smad4 (a transducer of TGFβ/BMP signaling) in the NCCs disrupts NCC migration into the stapes region in PA2, affecting stapes formation. These results indicate that region-specific endodermal signals direct formation of specific middle ear ossicles." [http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=30630826 Development]		* '''Region-specific endodermal signals direct {{neural crest}} cells to form the three {{middle ear}} ossicles'''{{#pmid:30630826\|PMID30630826}} "Defects in the middle ear ossicles - {{malleus}}, {{incus}} and {{stapes}} - can lead to conductive hearing loss. During development, {{neural crest}} cells (NCCs) migrate from the dorsal hindbrain to specific locations in {{pharyngeal arch}} (PA) 1 and 2, to form the malleus-incus and stapes, respectively. It is unclear how migratory NCCs reach their proper destination in the PA and initiate mesenchymal condensation to form specific ossicles. We show that secreted molecules sonic hedgehog ({{SHH}}) and bone morphogenetic protein 4 ({{BMP}}4) emanating from the pharyngeal {{endoderm}} are important in instructing region-specific NCC condensation to form malleus-incus and stapes, respectively, in mouse. Tissue-specific knockout of {{Shh}} in the pharyngeal endoderm or Smo (a transducer of SHH signaling) in NCCs causes the loss of malleus-incus condensation in PA1 but only affects the maintenance of stapes condensation in PA2. By contrast, knockout of {{Bmp}}4 in the pharyngeal endoderm or Smad4 (a transducer of TGFβ/BMP signaling) in the NCCs disrupts NCC migration into the stapes region in PA2, affecting stapes formation. These results indicate that region-specific endodermal signals direct formation of specific middle ear ossicles." [http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=30630826 Development]

Z8600021 at 07:28, 25 August 2020

2020-08-25T07:28:16Z

← Older revision		Revision as of 18:28, 25 August 2020
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	===Reviews===		===Reviews===

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	{{#pmid:26499980}}		{{#pmid:26499980}}

	{{#pmid:28293554}}		{{#pmid:28293554}}


	===Articles===		===Articles===

Z8600021 at 07:27, 25 August 2020

2020-08-25T07:27:24Z

← Older revision		Revision as of 18:27, 25 August 2020
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Z8600021 at 07:26, 25 August 2020

2020-08-25T07:26:41Z

← Older revision		Revision as of 18:26, 25 August 2020
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Z8600021 at 07:25, 25 August 2020

2020-08-25T07:25:08Z

← Older revision		Revision as of 18:25, 25 August 2020
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			{{#pmid:16492970}}

	===Search Pubmed===		===Search Pubmed===

Z8600021 at 13:01, 24 August 2020

2020-08-24T13:01:30Z

← Older revision		Revision as of 00:01, 25 August 2020
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			* '''The neocortical progenitor specification program is established through combined modulation of SHH and FGF signaling'''{{#pmid:32737167\|PMID32737167}} "Low levels of {{FGF}}15 control progenitor proliferation and differentiation during neocortical development but little is known on how {{FGF}}15 expression is maintained. Our studies identified {{SHH}} signaling as a critical activator of FGF15 expression during corticogenesis. We found that Sufu, via Gli3R, ensured low levels of FGF15 was expressed to prevent abnormal specification of neocortical progenitors. These studies advance our knowledge on the molecular mechanisms guiding the generation of specific neocortical neuronal lineages, their implications in neurodevelopmental diseases, and may guide future studies on how progenitor cells may be utilized for brain repair."

	* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} {{bone marrow}} stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}		* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} {{bone marrow}} stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}

	* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.		* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.

	* '''Region-specific endodermal signals direct {{neural crest}} cells to form the three {{middle ear}} ossicles'''{{#pmid:30630826\|PMID30630826}} "Defects in the middle ear ossicles - {{malleus}}, {{incus}} and {{stapes}} - can lead to conductive hearing loss. During development, {{neural crest}} cells (NCCs) migrate from the dorsal hindbrain to specific locations in {{pharyngeal arch}} (PA) 1 and 2, to form the malleus-incus and stapes, respectively. It is unclear how migratory NCCs reach their proper destination in the PA and initiate mesenchymal condensation to form specific ossicles. We show that secreted molecules sonic hedgehog ({{SHH}}) and bone morphogenetic protein 4 ({{BMP}}4) emanating from the pharyngeal {{endoderm}} are important in instructing region-specific NCC condensation to form malleus-incus and stapes, respectively, in mouse. Tissue-specific knockout of {{Shh}} in the pharyngeal endoderm or Smo (a transducer of SHH signaling) in NCCs causes the loss of malleus-incus condensation in PA1 but only affects the maintenance of stapes condensation in PA2. By contrast, knockout of {{Bmp}}4 in the pharyngeal endoderm or Smad4 (a transducer of TGFβ/BMP signaling) in the NCCs disrupts NCC migration into the stapes region in PA2, affecting stapes formation. These results indicate that region-specific endodermal signals direct formation of specific middle ear ossicles." [http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=30630826 Development]

	* '''Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion'''{{#pmid:29981310\|PMID29981310}} "{{Cleft palate}} is one of the most common craniofacial congenital defects in humans. It is associated with multiple genetic and environmental risk factors, including mutations in the genes encoding signaling molecules in the {{sonic hedgehog}} ({{SHH}}) pathway, which are risk factors for cleft palate in both humans and mice. However, the function of Shh signaling in the palatal epithelium during palatal fusion remains largely unknown. Although components of the Shh pathway are localized in the palatal epithelium, specific inhibition of Shh signaling in palatal epithelium does not affect palatogenesis. ...In this study, we discovered that constitutive activation of Hh signaling in the palatal epithelium results in submucous cleft palate and persistence of the medial edge epithelium (MEE). Further investigation revealed that precise downregulation of Shh signaling is required at a specific time point in the MEE during palatal fusion. Upregulation of Hh signaling in the palatal epithelium maintains the proliferation of MEE cells. This may be due to a dysfunctional p63/Irf6 regulatory loop. The resistance of MEE cells to apoptosis is likely conferred by enhancement of a cell adhesion network through the maintenance of p63 expression."

	* '''Structures of human Patched and its complex with native palmitoylated sonic hedgehog'''{{#pmid:29995851\|PMID29995851}} "Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms1-3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers2,4-6. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of 'native' sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 Å and 3.8 Å, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann-Pick C1 (NPC1) protein7. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N co-receptors8. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate."

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			* '''Region-specific endodermal signals direct {{neural crest}} cells to form the three {{middle ear}} ossicles'''{{#pmid:30630826\|PMID30630826}} "Defects in the middle ear ossicles - {{malleus}}, {{incus}} and {{stapes}} - can lead to conductive hearing loss. During development, {{neural crest}} cells (NCCs) migrate from the dorsal hindbrain to specific locations in {{pharyngeal arch}} (PA) 1 and 2, to form the malleus-incus and stapes, respectively. It is unclear how migratory NCCs reach their proper destination in the PA and initiate mesenchymal condensation to form specific ossicles. We show that secreted molecules sonic hedgehog ({{SHH}}) and bone morphogenetic protein 4 ({{BMP}}4) emanating from the pharyngeal {{endoderm}} are important in instructing region-specific NCC condensation to form malleus-incus and stapes, respectively, in mouse. Tissue-specific knockout of {{Shh}} in the pharyngeal endoderm or Smo (a transducer of SHH signaling) in NCCs causes the loss of malleus-incus condensation in PA1 but only affects the maintenance of stapes condensation in PA2. By contrast, knockout of {{Bmp}}4 in the pharyngeal endoderm or Smad4 (a transducer of TGFβ/BMP signaling) in the NCCs disrupts NCC migration into the stapes region in PA2, affecting stapes formation. These results indicate that region-specific endodermal signals direct formation of specific middle ear ossicles." [http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=30630826 Development]

			* '''Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion'''{{#pmid:29981310\|PMID29981310}} "{{Cleft palate}} is one of the most common craniofacial congenital defects in humans. It is associated with multiple genetic and environmental risk factors, including mutations in the genes encoding signaling molecules in the {{sonic hedgehog}} ({{SHH}}) pathway, which are risk factors for cleft palate in both humans and mice. However, the function of Shh signaling in the palatal epithelium during palatal fusion remains largely unknown. Although components of the Shh pathway are localized in the palatal epithelium, specific inhibition of Shh signaling in palatal epithelium does not affect palatogenesis. ...In this study, we discovered that constitutive activation of Hh signaling in the palatal epithelium results in submucous cleft palate and persistence of the medial edge epithelium (MEE). Further investigation revealed that precise downregulation of Shh signaling is required at a specific time point in the MEE during palatal fusion. Upregulation of Hh signaling in the palatal epithelium maintains the proliferation of MEE cells. This may be due to a dysfunctional p63/Irf6 regulatory loop. The resistance of MEE cells to apoptosis is likely conferred by enhancement of a cell adhesion network through the maintenance of p63 expression."

			* '''Structures of human Patched and its complex with native palmitoylated sonic hedgehog'''{{#pmid:29995851\|PMID29995851}} "Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms1-3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers2,4-6. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of 'native' sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 Å and 3.8 Å, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann-Pick C1 (NPC1) protein7. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N co-receptors8. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate."

	* '''Bergmann {{glia}}l Sonic hedgehog signaling activity is required for proper cerebellar cortical expansion and architecture'''{{#pmid:29792854\|PMID29792854}} "Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNCYFP-CreER line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNCYFP-CreER; SmoF/- (SmoCKO) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in SmoCKO CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture." {{SHH}}		* '''Bergmann {{glia}}l Sonic hedgehog signaling activity is required for proper cerebellar cortical expansion and architecture'''{{#pmid:29792854\|PMID29792854}} "Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNCYFP-CreER line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNCYFP-CreER; SmoF/- (SmoCKO) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in SmoCKO CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture." {{SHH}}

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	===Reviews===		===Reviews===

	{{$pmid:26499980}}		{{#pmid:26499980}}

	{{$pmid:28293554}}		{{#pmid:28293554}}

	===Articles===		===Articles===

	{{$pmid:32829689}}		{{#pmid:32829689}}

	{{$pmid:32826873}}		{{#pmid:32826873}}

	===Search Pubmed===		===Search Pubmed===

Z8600021 at 12:56, 24 August 2020

2020-08-24T12:56:27Z

← Older revision		Revision as of 23:56, 24 August 2020
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	<references/>		<references/>

			===Reviews===

			{{$pmid:26499980}}

			{{$pmid:28293554}}

			===Articles===

			{{$pmid:32829689}}

			{{$pmid:32826873}}

	===Search Pubmed===		===Search Pubmed===

Z8600021 at 04:37, 23 Ocak 2020

2020-01-23T04:37:31Z

← Older revision		Revision as of 15:37, 23 Ocak 2020
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	* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} bone marrow stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}		* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} {{bone marrow}} stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}

	* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.		* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.

Z8600021 at 08:24, 1 Ocak 2020

2020-01-01T08:24:16Z

← Older revision		Revision as of 19:24, 1 Ocak 2020
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	\|		\|
	* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of rabbit bone marrow stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}		* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} bone marrow stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}

	* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.		* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.
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	Model for GATA6 action Patterning developing Hindlimb Buds{{#pmid:24415953\|PMID4415953}}		Model for GATA6 action Patterning developing Hindlimb Buds{{#pmid:24415953\|PMID4415953}}

			===Cartilage===

			'''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of {{rabbit}} bone marrow stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation."


			:'''Links:''' {{cartilage}}

	===Face===		===Face===
	SHH is secreted by the forebrain neuroectoderm and the facial ectoderm for upper face and nasofrontal bud development.{{#pmid:15979605\|PMID15979605}}		SHH is secreted by the forebrain neuroectoderm and the facial ectoderm for upper face and nasofrontal bud development.{{#pmid:15979605\|PMID15979605}}

Z8600021 at 08:20, 1 Ocak 2020

2020-01-01T08:20:29Z

← Older revision		Revision as of 19:20, 1 Ocak 2020
Line 23:		Line 23:
	\|-bgcolor="F5FAFF"		\|-bgcolor="F5FAFF"
	\|		\|
			* '''Sonic hedgehog promotes chondrogenesis of rabbit bone marrow stem cells in a rotary cell culture system'''{{#pmid:31401976\|PMID31401976}} "Sonic hedgehog (Shh) is an important signalling protein involved in the induction of early cartilaginous differentiation. Herein, we demonstrate that Shh markedly induces {{chondrogenesis}} of rabbit bone marrow stromal cells (BMSCs) under microgravity conditions, and promotes cartilage regeneration. In the rotary cell culture system (RCCS), chondrogenic differentiation was revealed by stronger Toluidine Blue and collagen II immunohistochemical staining in the Shh transfection group, and chondroinductive activity of Shh was equivalent to that of TGF-β. Western blotting and qRT-PCR analysis results verified the stronger expression of Sox9, aggrecan (ACAN), and collagen II in rabbit BMSCs treated with Shh or TGF-β in a microgravity environment. Low levels of chondrogenic hypertrophy, osteogenesis, and adipogenesis-related factors were detected in all groups. After transplantation in vivo, histological analysis revealed a significant improvement in cartilage and subchondral repair in the Shh transfection group. These results suggested that Shh signalling promoted chondrogenesis in rabbit BMSCs under microgravity conditions equivalent to TGF-β, and improved the early stages of the repair of cartilage and subchondral defects. Furthermore, RCCS provided a dynamic culture microenvironment conducive for cell proliferation, aggregation and differentiation." {{cartilage}}

	* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.		* '''SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization'''{{#pmid:31685615\|PMID31685615}} "Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the {{forebrain}} and {{hypothalamus}} in the mouse embryo, and caused a craniofacial abnormality similar to human {{holoprosencephaly}} (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.