Musculoskeletal System - Limb Development - Revision history

Z8600021 at 00:08, 18 December 2021

2021-12-18T00:08:46Z

← Older revision		Revision as of 10:08, 18 December 2021
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	===Reviews===		===Reviews===
			{{#pmid:32212250}}

	{{#pmid:32079177}}		{{#pmid:32079177}}

Z8600021 at 00:07, 18 December 2021

2021-12-18T00:07:38Z

← Older revision		Revision as of 10:07, 18 December 2021
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			* '''Conserved and species-specific chromatin remodeling and regulatory dynamics during {{mouse}} and {{chicken}} limb bud development'''{{#pmid:34584102\|PMID34584102}} "Chromatin remodeling and genomic alterations impact spatio-temporal regulation of gene expression, which is central to embryonic development. The analysis of mouse and chicken limb development provides important insights into the morphoregulatory mechanisms, however little is known about the regulatory differences underlying their morphological divergence. Here, we identify the underlying shared and species-specific epigenomic and genomic variations. In mouse forelimb buds, we observe striking synchrony between the temporal dynamics of chromatin accessibility and gene expression, while their divergence in chicken wing buds uncovers species-specific regulatory heterochrony. In silico mapping of transcription factor binding sites and computational footprinting establishes the developmental time-restricted transcription factor-DNA interactions. Finally, the construction of target gene networks for HAND2 and GLI3 transcriptional regulators reveals both conserved and species-specific interactions."

	* '''The formation of the thumb requires direct modulation of Gli3 transcription by {{Hox}}a13'''{{#pmid:31896583\|PMID31896583}} "In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5'Hoxd second expression phase, thereby establishing anterior-posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution." {{Hox}}		* '''The formation of the thumb requires direct modulation of Gli3 transcription by {{Hox}}a13'''{{#pmid:31896583\|PMID31896583}} "In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5'Hoxd second expression phase, thereby establishing anterior-posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution." {{Hox}}

Z8600021 at 22:53, 1 December 2021

2021-12-01T22:53:09Z

← Older revision		Revision as of 08:53, 2 December 2021
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	* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates {{chondrogenesis}} during {{limb}} development'''{{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."		* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates {{chondrogenesis}} during {{limb}} development'''{{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."

	* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."

	* '''Review - The {{chicken}} limb - embryology, genetics and teratology'''{{#pmid:29616743\|PMID29616743}} "Early studies elucidated the fundamental embryology of the limb and identified the key signalling regions that govern its development. The chick limb became a leading model for exploring the concept of positional information and understanding how patterns of differentiated cells and tissues develop in vertebrate embryos. When developmentally important molecules began to be identified, experiments in chick limbs were crucial for bridging embryology and molecular biology. The embryological mechanisms and molecular basis of limb development are largely conserved in mammals, including humans, and uncovering these molecular networks provides links to clinical genetics. We emphasise the important contributions of naturally occurring chick mutants to elucidating limb embryology and identifying novel developmentally important genes. In addition, we consider how the chick limb has been used to study mechanisms involved in teratogenesis with a focus on thalidomide. These studies on chick embryos have given insights into how limb defects can be caused by both genetic changes and chemical insults and therefore are of great medical significance." More? {{chicken}}

			* '''Review - The {{chicken}} limb - embryology, genetics and teratology'''{{#pmid:29616743\|PMID29616743}}
	\|}		\|}

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	\|-		\|-
	\| {{Older papers}}		\| {{Older papers}}
			* '''Analysis of a {{limb}}-specific regulatory element in the promoter of the link protein gene'''{{#pmid:31470976\|PMID31470976}} "Link protein is encoded by the Hapln1 gene and is a prototypical protein found in the {{cartilage}} matrix. It acts as an important component of the endochondral skeleton during early development. To study its transcriptional regulation, promoter fragments derived from the link protein gene were coupled to the β-galactosidase reporter and used to study in vivo transgene expression in mice. In day 15.5 mouse embryos, a link promoter fragment spanning -1020 to +40 nucleotides demonstrated highly specific β-galactosidase staining of skeletal structures, including the appendicular and axial cartilaginous tissues. Two shorter promoter fragments, spanning -690 to +40 and -315 to +40 nucleotides, demonstrated limb- and genitalia-specific expression resembling that of homeodomain-regulated tissues. Bioinformatic analysis revealed a highly conserved, {{Hox}}-like binding site (HLBS) at approximately -220 bp of the promoter, shared by both constructs, which contained the Hox-core consensus sequence TAATTA. Electromobility shift assays demonstrated binding of {{Hox}}-B4 recombinant protein to the HLBS, which was eliminated with nucleotide substitutions within the core-binding element. Co-transfection analysis of the HLBS demonstrated a 22-fold transcriptional activation by HoxA9 expression, which was ablated with a substitution within the core HLBS element. Together these findings establish promoter regions within the link protein gene that are important for in vivo expression and identify the potential role of homeodomain-containing proteins in controlling {{cartilage}} and {{limb}} gene expression."

			* '''Review - The {{chicken}} limb - embryology, genetics and teratology'''{{#pmid:29616743\|PMID29616743}} "Early studies elucidated the fundamental embryology of the limb and identified the key signalling regions that govern its development. The chick limb became a leading model for exploring the concept of positional information and understanding how patterns of differentiated cells and tissues develop in vertebrate embryos. When developmentally important molecules began to be identified, experiments in chick limbs were crucial for bridging embryology and molecular biology. The embryological mechanisms and molecular basis of limb development are largely conserved in mammals, including humans, and uncovering these molecular networks provides links to clinical genetics. We emphasise the important contributions of naturally occurring chick mutants to elucidating limb embryology and identifying novel developmentally important genes. In addition, we consider how the chick limb has been used to study mechanisms involved in teratogenesis with a focus on thalidomide. These studies on chick embryos have given insights into how limb defects can be caused by both genetic changes and chemical insults and therefore are of great medical significance." More? {{chicken}}


	* '''A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in {{triphalangeal thumb}}-polysyndactyly syndrome'''{{#pmid:29543231\|PMID29543231}} "The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in {{dog}}s and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. The mutation was linked to chromosome {{Chr7}}q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud ({{ME11.5}})."		* '''A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in {{triphalangeal thumb}}-polysyndactyly syndrome'''{{#pmid:29543231\|PMID29543231}} "The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in {{dog}}s and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. The mutation was linked to chromosome {{Chr7}}q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud ({{ME11.5}})."

Z8600021 at 02:01, 16 March 2020

2020-03-16T02:01:35Z

← Older revision		Revision as of 12:01, 16 March 2020
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	:'''Links:''' [[Developmental_Signals_-_Fibroblast_Growth_Factor\|Fibroblast Growth Factor]] \| ~~[[Developmental_Signals_-_Sonic_hedgehog\|~~Sonic hedgehog~~]] \| [[Developmental_Signals_-_Wnt~~\|Wnt]] \| [http://www.ncbi.nlm.nih.gov/omim/602407 Hand2] \| [http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim&term=Hand2 OMIM]		:'''Links:''' [[Developmental_Signals_-_Fibroblast_Growth_Factor\|Fibroblast Growth Factor]] \| {{Sonic hedgehog}} \| {{Wnt}} \| [http://www.ncbi.nlm.nih.gov/omim/602407 Hand2] \| [http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim&term=Hand2 OMIM]

	== References ==		== References ==

Z8600021 at 01:54, 16 March 2020

2020-03-16T01:54:14Z

← Older revision		Revision as of 11:54, 16 March 2020
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	{{Musculoskeletal Links}}		{{Musculoskeletal Links}}


	~~{\| class="wikitable mw-collapsible mw-collapsed"~~
	~~! [[Historic Embryology_Papers\|'''Historic Papers''']]~~
	\|-
	\| [[Book_-_Human_Embryology_and_Morphology_20\|1902 Limbs]] \| [[Book_-_Manual_of_Human_Embryology_12#The_Musculature_of_the_Extremities\|1910 Limb Muscles]] \| [[Book_-_Contributions_to_Embryology_Carnegie_Institution_No.70\|1922 Pig Limb Vasculature]]
	\|}

	:{{Factor Links}}		:{{Factor Links}}

Z8600021 at 01:51, 16 March 2020

2020-03-16T01:51:26Z

← Older revision		Revision as of 11:51, 16 March 2020
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	Development of the other parts of the appendicular skeleton, [[Musculoskeletal System - Shoulder Development\|shoulder]] and [[Musculoskeletal System - Pelvis Development\|pelvis]], are described on separate pages.		Development of the other parts of the appendicular skeleton, [[Musculoskeletal System - Shoulder Development\|shoulder]] and [[Musculoskeletal System - Pelvis Development\|pelvis]], are described on separate pages.

			{{Limb Links}}

	{{Musculoskeletal Links}}		{{Musculoskeletal Links}}

Z8600021 at 09:53, 9 March 2020

2020-03-09T09:53:25Z

← Older revision		Revision as of 19:53, 9 March 2020
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	* '''Review - The {{chicken}} limb - embryology, genetics and teratology'''{{#pmid:29616743\|PMID29616743}} "Early studies elucidated the fundamental embryology of the limb and identified the key signalling regions that govern its development. The chick limb became a leading model for exploring the concept of positional information and understanding how patterns of differentiated cells and tissues develop in vertebrate embryos. When developmentally important molecules began to be identified, experiments in chick limbs were crucial for bridging embryology and molecular biology. The embryological mechanisms and molecular basis of limb development are largely conserved in mammals, including humans, and uncovering these molecular networks provides links to clinical genetics. We emphasise the important contributions of naturally occurring chick mutants to elucidating limb embryology and identifying novel developmentally important genes. In addition, we consider how the chick limb has been used to study mechanisms involved in teratogenesis with a focus on thalidomide. These studies on chick embryos have given insights into how limb defects can be caused by both genetic changes and chemical insults and therefore are of great medical significance." More? {{chicken}}		* '''Review - The {{chicken}} limb - embryology, genetics and teratology'''{{#pmid:29616743\|PMID29616743}} "Early studies elucidated the fundamental embryology of the limb and identified the key signalling regions that govern its development. The chick limb became a leading model for exploring the concept of positional information and understanding how patterns of differentiated cells and tissues develop in vertebrate embryos. When developmentally important molecules began to be identified, experiments in chick limbs were crucial for bridging embryology and molecular biology. The embryological mechanisms and molecular basis of limb development are largely conserved in mammals, including humans, and uncovering these molecular networks provides links to clinical genetics. We emphasise the important contributions of naturally occurring chick mutants to elucidating limb embryology and identifying novel developmentally important genes. In addition, we consider how the chick limb has been used to study mechanisms involved in teratogenesis with a focus on thalidomide. These studies on chick embryos have given insights into how limb defects can be caused by both genetic changes and chemical insults and therefore are of great medical significance." More? {{chicken}}

	* '''A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in {{triphalangeal thumb}}-polysyndactyly syndrome'''{{#pmid:29543231\|PMID29543231}} "The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in {{dog}}s and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. The mutation was linked to chromosome {{Chr7}}q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud ({{ME11.5}})."

	\|}		\|}
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	\|-		\|-
	\| {{Older papers}}		\| {{Older papers}}
			* '''A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in {{triphalangeal thumb}}-polysyndactyly syndrome'''{{#pmid:29543231\|PMID29543231}} "The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in {{dog}}s and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. The mutation was linked to chromosome {{Chr7}}q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud ({{ME11.5}})."

	* '''Species-specific Posture of Human Foetus in Late First Trimester'''{{#pmid:29311655\|PMID29311655}} The ontogeny associated with the arm-hanging posture, which is considered ape-specific, remains unknown. To examine its ontogeny, we measured foetal movements of 62 human foetuses aged 10-20 gestation weeks using four-dimensional sonography. We observed that the first-trimester foetuses show this particular species-specific posture. After 11 weeks of gestation, all foetuses showed the arm-hanging posture, and the posture was most frequently observed at 14-16 weeks of gestation. Moreover, this posture often involved extension of both arms and both legs, indicating that it is not myogenic but neurogenic. Furthermore, early ontogeny suggests that it originates because of subcortical activity. Such posture extension bias and persistence indicates that vestibulospinal tract maturation involves the ontogeny of arm-hanging posture during 14-16 weeks of gestation." {{spinal cord}}		* '''Species-specific Posture of Human Foetus in Late First Trimester'''{{#pmid:29311655\|PMID29311655}} The ontogeny associated with the arm-hanging posture, which is considered ape-specific, remains unknown. To examine its ontogeny, we measured foetal movements of 62 human foetuses aged 10-20 gestation weeks using four-dimensional sonography. We observed that the first-trimester foetuses show this particular species-specific posture. After 11 weeks of gestation, all foetuses showed the arm-hanging posture, and the posture was most frequently observed at 14-16 weeks of gestation. Moreover, this posture often involved extension of both arms and both legs, indicating that it is not myogenic but neurogenic. Furthermore, early ontogeny suggests that it originates because of subcortical activity. Such posture extension bias and persistence indicates that vestibulospinal tract maturation involves the ontogeny of arm-hanging posture during 14-16 weeks of gestation." {{spinal cord}}

Z8600021 at 05:47, 9 March 2020

2020-03-09T05:47:31Z

← Older revision		Revision as of 15:47, 9 March 2020
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	===Reviews===		===Reviews===
			{{#pmid:32079177}}

	{{#pmid:26249743}}		{{#pmid:26249743}}

Z8600021 at 01:13, 16 Ocak 2020

2020-01-16T01:13:50Z

← Older revision		Revision as of 11:13, 16 Ocak 2020
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	* '''The formation of the thumb requires direct modulation of Gli3 transcription by {{Hox}}a13'''{{#pmid:31896583\|PMID31896583}} "In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5'Hoxd second expression phase, thereby establishing anterior-posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution." {{Hox}}		* '''The formation of the thumb requires direct modulation of Gli3 transcription by {{Hox}}a13'''{{#pmid:31896583\|PMID31896583}} "In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5'Hoxd second expression phase, thereby establishing anterior-posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution." {{Hox}}

Z8600021 at 01:13, 16 Ocak 2020

2020-01-16T01:13:17Z

← Older revision		Revision as of 11:13, 16 Ocak 2020
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			* '''The formation of the thumb requires direct modulation of Gli3 transcription by {{Hox}}a13'''{{#pmid:31896583\|PMID31896583}} "In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5'Hoxd second expression phase, thereby establishing anterior-posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution." {{Hox}}

	* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates {{chondrogenesis}} during {{limb}} development'''{{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."		* '''L-type voltage-gated Ca2+ channel CaV1.2 regulates {{chondrogenesis}} during {{limb}} development'''{{#pmid:31591237\|PMID31591237}} "All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation."

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	* '''A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in {{triphalangeal thumb}}-polysyndactyly syndrome'''{{#pmid:29543231\|PMID29543231}} "The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in {{dog}}s and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. The mutation was linked to chromosome {{Chr7}}q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud ({{ME11.5}})."		* '''A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in {{triphalangeal thumb}}-polysyndactyly syndrome'''{{#pmid:29543231\|PMID29543231}} "The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in {{dog}}s and humans. Here, we report the first case of triphalangeal thumb-polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. The mutation was linked to chromosome {{Chr7}}q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud ({{ME11.5}})."

	* '''Species-specific Posture of Human Foetus in Late First Trimester'''{{#pmid:29311655\|PMID29311655}} The ontogeny associated with the arm-hanging posture, which is considered ape-specific, remains unknown. To examine its ontogeny, we measured foetal movements of 62 human foetuses aged 10-20 gestation weeks using four-dimensional sonography. We observed that the first-trimester foetuses show this particular species-specific posture. After 11 weeks of gestation, all foetuses showed the arm-hanging posture, and the posture was most frequently observed at 14-16 weeks of gestation. Moreover, this posture often involved extension of both arms and both legs, indicating that it is not myogenic but neurogenic. Furthermore, early ontogeny suggests that it originates because of subcortical activity. Such posture extension bias and persistence indicates that vestibulospinal tract maturation involves the ontogeny of arm-hanging posture during 14-16 weeks of gestation." {{spinal cord}}

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			* '''Species-specific Posture of Human Foetus in Late First Trimester'''{{#pmid:29311655\|PMID29311655}} The ontogeny associated with the arm-hanging posture, which is considered ape-specific, remains unknown. To examine its ontogeny, we measured foetal movements of 62 human foetuses aged 10-20 gestation weeks using four-dimensional sonography. We observed that the first-trimester foetuses show this particular species-specific posture. After 11 weeks of gestation, all foetuses showed the arm-hanging posture, and the posture was most frequently observed at 14-16 weeks of gestation. Moreover, this posture often involved extension of both arms and both legs, indicating that it is not myogenic but neurogenic. Furthermore, early ontogeny suggests that it originates because of subcortical activity. Such posture extension bias and persistence indicates that vestibulospinal tract maturation involves the ontogeny of arm-hanging posture during 14-16 weeks of gestation." {{spinal cord}}

	* '''Digits and fin rays share common developmental histories'''{{#pmid:27533041\|PMID27533041}} "Here, we provide a functional analysis, using CRISPR/Cas9 and fate mapping, of 5' hox genes and enhancers in zebrafish that are indispensable for the development of the wrists and digits of tetrapods. We show that cells marked by the activity of an autopodial hoxa13 enhancer exclusively form elements of the fin fold, including the osteoblasts of the dermal rays. In hox13 knockout fish, we find that a marked reduction and loss of fin rays is associated with an increased number of endochondral distal radials. These discoveries reveal a cellular and genetic connection between the fin rays of fish and the digits of tetrapods and suggest that digits originated via the transition of distal cellular fates."		* '''Digits and fin rays share common developmental histories'''{{#pmid:27533041\|PMID27533041}} "Here, we provide a functional analysis, using CRISPR/Cas9 and fate mapping, of 5' hox genes and enhancers in zebrafish that are indispensable for the development of the wrists and digits of tetrapods. We show that cells marked by the activity of an autopodial hoxa13 enhancer exclusively form elements of the fin fold, including the osteoblasts of the dermal rays. In hox13 knockout fish, we find that a marked reduction and loss of fin rays is associated with an increased number of endochondral distal radials. These discoveries reveal a cellular and genetic connection between the fin rays of fish and the digits of tetrapods and suggest that digits originated via the transition of distal cellular fates."