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

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

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A specific mutation in the distant sonic hedgehog (SHH)cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb

Human Mutation ◽

10.1002/humu.21142 ◽

2010 ◽

Vol 31 (1) ◽

pp. 81-89 ◽

Cited By ~ 88

Author(s):

Dagmar Wieczorek ◽

Barbara Pawlik ◽

Yun Li ◽

Nurten A. Akarsu ◽

Almuth Caliebe ◽

...

Keyword(s):

Sonic Hedgehog ◽

Specific Mutation ◽

Preaxial Polydactyly ◽

Triphalangeal Thumb

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

PLoS Genetics ◽

10.1371/journal.pgen.1009982 ◽

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.

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

10.1101/2020.06.17.158501 ◽

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.

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

Journal of Hand Surgery (European Volume) ◽

10.1177/1753193418762959 ◽

2018 ◽

Vol 44 (1) ◽

pp. 43-50 ◽

Cited By ~ 4

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.

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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

BioMed Research International ◽

10.1155/2018/1573871 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 4

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.

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