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 ◽  
...  

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.

2020 ◽  
Author(s):  
Deepika Sharma ◽  
Anthony J. Mirando ◽  
Abigail Leinroth ◽  
Jason T. Long ◽  
Courtney M. Karner ◽  
...  

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.


2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Feixue Li ◽  
Guoquan Fu ◽  
Ying Liu ◽  
Xiaoping Miao ◽  
Yan Li ◽  
...  

ABSTRACT Mandibular patterning information initially resides in the epithelium during development. However, how transcriptional regulation of epithelium-derived signaling controls morphogenesis of the mandible remains elusive. Using Shh Cre to target the mandibular epithelium, we ablated transcription factor Islet1, resulting in a distally truncated mandible via unbalanced cell apoptosis and decreased cell proliferation in the distal mesenchyme. Loss of Islet1 caused a lack of cartilage at the distal tip, leading the fusion of two growing mandibular elements surrounding the rostral process of Meckel's cartilage. Loss of Islet1 results in dysregulation of mesenchymal genes important for morphogenesis of the mandibular arch. We revealed that Islet1 is required for the activation of epithelial β-catenin signaling via repression of Wnt antagonists. Reactivation of β-catenin in the epithelium of the Islet1 mutant rescued mandibular morphogenesis through sonic hedgehog (SHH) signaling to the mesenchyme. Furthermore, overexpression of a transgenic hedgehog ligand in the epithelium also partially restored outgrowth of the mandible. These data reveal functional roles for an ISLET1-dependent network integrating β-catenin/SHH signals in mesenchymal cell survival and outgrowth of the mandible during development.


2019 ◽  
Vol 234 (10) ◽  
pp. 18970-18984 ◽  
Author(s):  
Xiaojing Xia ◽  
Xin Wang ◽  
Shouping Zhang ◽  
Yi Zheng ◽  
Lei Wang ◽  
...  

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e63226 ◽  
Author(s):  
Olga Bermudez ◽  
Elisabeth Hennen ◽  
Ina Koch ◽  
Michael Lindner ◽  
Oliver Eickelberg

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Joseph Pickering ◽  
Kavitha Chinnaiya ◽  
Matthew Towers

A fundamental question is how proliferation and growth are timed during embryogenesis. Although it has been suggested that the cell cycle could be a timer, the underlying mechanisms remain elusive. Here we describe a cell cycle timer that operates in Sonic hedgehog (Shh)-expressing polarising region cells of the chick wing bud. Our data are consistent with Shh signalling stimulating polarising region cell proliferation via Cyclin D2, and then inhibiting proliferation via a Bmp2-p27kip1 pathway. When Shh signalling is blocked, polarising region cells over-proliferate and form an additional digit, which can be prevented by applying Bmp2 or by inhibiting D cyclin activity. In addition, Bmp2 also restores posterior digit identity in the absence of Shh signalling, thus indicating that it specifies antero-posterior (thumb to little finger) positional values. Our results reveal how an autoregulatory cell cycle timer integrates growth and specification and are widely applicable to many tissues.


Development ◽  
1997 ◽  
Vol 124 (1) ◽  
pp. 53-63 ◽  
Author(s):  
S. Bellusci ◽  
Y. Furuta ◽  
M.G. Rush ◽  
R. Henderson ◽  
G. Winnier ◽  
...  

Branching morphogenesis of the embryonic lung requires interactions between the epithelium and the mesenchyme. Previously, we reported that Sonic hedgehog (Shh) transcripts are present in the epithelium of the developing mouse lung, with highest levels in the terminal buds. Here, we report that transcripts of mouse patched (Ptc), the homologue of a Drosophila gene encoding a putative transmembrane protein required for hedgehog signaling, are expressed at high levels in the mesenchyme adjacent to the end buds. To investigate the function of SHH in lung development, Shh was overexpressed throughout the distal epithelium, using the surfactant protein-C (SP-C)-enhancer/promoter. Beginning around 16.5 dpc, when Shh and Ptc RNA levels are normally both declining, this treatment caused an increase in the ratio of interstitial mesenchyme to epithelial tubules in transgenic compared to normal lungs. Transgenic newborn mice die soon after birth. Histological analysis of the lungs at the light and electron microscope level shows an abundance of mesenchyme and the absence of typical alveoli. In vivo BrdU labeling indicates that Shh overexpression results in increased mesenchymal and epithelial cell proliferation at 16.5 and 17.5 dpc. However, analysis of CC-10 and SP-C expression reveals no significant inhibition in the differentiation of proximal and distal epithelial cells. The expression of genes potentially regulated by SHH was also examined. No difference could be observed between transgenic and control lungs in either the level or distribution of Bmp4, Wnt2 and Fgf7 RNA. By contrast, Ptc is clearly upregulated in the transgenic lung. These results thus establish a role for SHH in lung morphogenesis, and suggest that SHH normally regulates lung mesenchymal cell proliferation in vivo.


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