scholarly journals Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly

2007 ◽  
Vol 17 (7) ◽  
pp. 978-985 ◽  
Author(s):  
Laura A. Lettice ◽  
Alison E. Hill ◽  
Paul S. Devenney ◽  
Robert E. Hill
Keyword(s):  
Sonic Hedgehog ◽  
Point Mutations ◽  
Preaxial Polydactyly

scholarly journals Zone of Polarizing Activity Regulatory Sequence Mutations/Duplications with Preaxial Polydactyly and Longitudinal Preaxial Ray Deficiency in the Phenotype: A Review of Human Cases, Animal Models, and Insights Regarding the Pathogenesis

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Mohammad M. Al-Qattan
Keyword(s):  
Developmental Biology ◽  
Animal Models ◽  
Sonic Hedgehog ◽  
Ectopic Expression ◽  
Point Mutations ◽  
Limb Bud ◽  
Regulatory Sequence ◽  
Preaxial Polydactyly ◽  
Zone Of Polarizing Activity

Clinicians and scientists interested in developmental biology have viewed preaxial polydactyly (PPD) and longitudinal preaxial ray deficiency (LPAD) as two different entities. Point mutations and duplications in the zone of polarizing activity regulatory sequence (ZRS) are associated with anterior ectopic expression of Sonic Hedgehog (SHH) in the limb bud and usually result in a PPD phenotype. However, some of these mutations/duplications also have LPAD in the phenotype. This unusual PPD-LPAD association in ZRS mutations/duplications has not been specifically reviewed in the literature. The author reviews this unusual entity and gives insights regarding its pathogenesis.

scholarly journals Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly

2007 ◽  
Vol 143A (1) ◽  
pp. 27-32 ◽  
Author(s):  
Christina A. Gurnett ◽  
Anne M. Bowcock ◽  
Frederick R. Dietz ◽  
Jose A. Morcuende ◽  
Jeffrey C. Murray ◽  
...  
Keyword(s):  
Long Range ◽  
Point Mutations ◽  
Preaxial Polydactyly ◽  
Triphalangeal Thumb

The association between preaxial polydactyly and radial longitudinal deficiency in syndromic cases: a report on nine families

2018 ◽  
Vol 43 (7) ◽  
pp. 744-750 ◽  
Author(s):  
Mohammad M. Al-Qattan
Keyword(s):  
Sonic Hedgehog ◽  
Level Of Evidence ◽  
Preaxial Polydactyly ◽  
Radial Longitudinal Deficiency

Preaxial polydactyly and radial longitudinal deficiency are usually viewed as two different entities. We present nine families with different disorders in which both preaxial polydactyly and radial longitudinal deficiency were seen in the phenotype. This indicates that both entities may be caused by the same developmental error or insult. The pathogenesis is complex and may be related to the interactions of two signalling loops: the first loop (named as the radial longitudinal deficiency loop) contains genes/proteins responsible for the development of the radial ray; and the second loop (named as the preaxial polydactyly loop) contains the Sonic Hedgehog involved in the pathogenesis of preaxial polydactyly. This entity is named as the preaxial polydactyly–radial longitudinal deficiency association and should be included in the description of the preaxial polydactyly spectrum. Level of evidence: IV

The pathogenesis of preaxial polydactyly: Anatomical insights using a silkie chicken model with sonic hedgehog mutation enhancement

2014 ◽  
Vol 67 (11) ◽  
pp. 1611
Author(s):  
Edward J. Johnson ◽  
David M. Neely ◽  
Ian C. Dunn ◽  
Wee L. Lam ◽  
Megan G. Davey
Keyword(s):  
Sonic Hedgehog ◽  
Preaxial Polydactyly ◽  
Chicken Model

scholarly journals HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009982
Author(s):  
Deepika Sharma ◽  
Anthony J. Mirando ◽  
Abigail Leinroth ◽  
Jason T. Long ◽  
Courtney M. Karner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Mesenchymal Cell ◽  
Digit Number ◽  
Preaxial Polydactyly ◽  
Molecular Approaches ◽  
Downstream Effector ◽  
Signaling Axis

Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.

HES1 is a Critical Mediator of the SHH-GLI3 Axis in Regulating Digit Number

2020 ◽  
Author(s):  
Deepika Sharma ◽  
Anthony J. Mirando ◽  
Abigail Leinroth ◽  
Jason T. Long ◽  
Courtney M. Karner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Transcriptional Regulator ◽  
Mesenchymal Cell ◽  
Digit Number ◽  
Preaxial Polydactyly ◽  
Molecular Approaches ◽  
Comprehensive Framework ◽  
Anterior Posterior

ABSTRACTSonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. Anterior-posterior SHH/GLI3 signaling gradients regulate cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a key transcriptional regulator downstream of SHH/GLI signaling capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings fill gaps in knowledge regarding digit number and patterning, while creating a comprehensive framework for our molecular understanding of critical mediators of SHH/GLI3 signaling.

scholarly journals Experimental evidence that preaxial polydactyly and forearm radial deficiencies may share a common developmental origin

2018 ◽  
Vol 44 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Wee L. Lam ◽  
Julia D. H. Oh ◽  
Edward J. Johnson ◽  
Sandra Poyatos Pertinez ◽  
Chloe Stephens ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Experimental Evidence ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Experimental Conditions ◽  
Hedgehog Signalling ◽  
Preaxial Polydactyly ◽  
Hedgehog Signalling Pathway ◽  
Sonic Hedgehog Signalling ◽  
Radial Aplasia

Preaxial polydactyly is a congenital hand anomaly predominantly of sporadic occurrence, which is frequently associated with abnormalities of the Sonic hedgehog signalling pathway. In experimentally induced preaxial polydactyly, radial aplasia is also frequently observed. To determine if there is a correlation between preaxial polydactyly and radial aplasia, we induced ectopic Sonic hedgehog signalling during chicken limb development with application of a smoothened-agonist (SAG) or retinoic acid. Application of SAG caused malformations in 71% limbs including preaxial polydactyly (62%) and forearm abnormalities (43%). Retinoic acid application induced malformations in 56% of limb including preaxial polydactyly (45%) and forearm abnormalities (50%). Radial dysplasia and ulnar dimelia were observed in both experimental conditions. We demonstrate that ectopic Sonic hedgehog signalling may cause both preaxial polydactyly and predictable forearm anomalies and that these conditions could potentially be classified as one embryological group. We propose a unifying model based on known models of ectopic Sonic hedgehog signalling.

Identification of a Novel Sonic Hedgehog Response Element in the Chicken Ovalbumin Upstream Promoter-Transcription Factor II Promoter

1997 ◽  
Vol 11 (10) ◽  
pp. 1458-1466 ◽  
Author(s):  
Venkatesh Krishnan ◽  
Gerard Elberg ◽  
Ming-Jer Tsai ◽  
Sophia Y. Tsai
Keyword(s):  
Transcription Factor ◽  
Motor Neuron ◽  
Sonic Hedgehog ◽  
Point Mutations ◽  
Protein S ◽  
Response Element ◽  
Enhancer Element ◽  
Factor Ii ◽  
Upstream Promoter ◽  
Chicken Ovalbumin

Abstract Sonic hedgehog (Shh) is a secreted morphogen that regulates dorso-ventral patterning within the neural tube during embryonic development. It is well established that Shh can induce motor-neuron differentiation that coincides with the appearance of specific motor-neuron markers including chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) and Isl1. However, the mechanism of Shh-induced signaling pathway in vertebrates is not clearly defined. In this report we have identified COUP-TFII as a target gene for Shh. In addition we have used a 1.6-kb region of the COUP-TFII promoter to identify a target element that mediates the Shh-induced activity. Extensive deletions introduced within this region have further enabled us to identify a novel sonic hedgehog response element (ShhRE) in the COUP-TFII promoter. Point mutations introduced within the ShhRE reveal some key nucleotides that are essential for protein(s)-binding activity. Finally, the ShhRE is capable of functioning as a true enhancer element and can mediate Shh-induced transactivation of reporter gene via a heterologous promoter.

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