Abstract
The role of basal suppression of the sonic hedgehog (Shh) pathway and its interaction with Indian hedgehog (Ihh) signaling during limb/ skeletal morphogenesis is not well understood. The orphan G protein-coupled receptor Gpr161 localizes to primary cilia and functions as a negative regulator of Shh signaling by promoting Gli transcriptional repressor versus activator formation. Here, we show that forelimb buds are not formed in Gpr161 knockout mouse embryos despite establishment of prospective limb fields. Limb-specific deletion of Gpr161 resulted in prematurely expanded Shh signaling and ectopic Shh-dependent patterning defects resulting in polysyndactyly. In addition, endochondral bone formation in forearms, including formation of both trabecular bone and bone collar was prevented. Endochondral bone formation defects resulted from accumulation of proliferating round/periarticular-like chondrocytes, lack of differentiation into columnar chondrocytes, and corresponding absence of Ihh signaling. Gpr161 deficiency in craniofacial mesenchyme also prevented intramembranous bone formation in calvarium. Defects in limb patterning, endochondral and intramembranous skeletal morphogenesis were suppressed in the absence of cilia. Overall, Gpr161 promotes forelimb formation, regulates limb patterning, prevents periarticular chondrocyte proliferation and drives osteoblastogenesis in intramembranous bones in a cilium-dependent manner.
| Original language | English (US) |
|---|---|
| Article number | dev154054 |
| Journal | Development (Cambridge) |
| Volume | 145 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2018 |
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Keywords
- Endochondral bone
- G protein-coupled receptor
- Hedgehog
- Intramembranous bone
- Limb
- Primary cilia
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology
Cite this
The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner. / Hwang, Sun Hee; White, Kevin A.; Somatilaka, Bandarigoda N.; Shelton, John M.; Richardson, James A.; Mukhopadhyay, Saikat.
In: Development (Cambridge), Vol. 145, No. 1, dev154054, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner
AU - Hwang, Sun Hee
AU - White, Kevin A.
AU - Somatilaka, Bandarigoda N.
AU - Shelton, John M.
AU - Richardson, James A.
AU - Mukhopadhyay, Saikat
PY - 2018/1/1
Y1 - 2018/1/1
N2 - The role of basal suppression of the sonic hedgehog (Shh) pathway and its interaction with Indian hedgehog (Ihh) signaling during limb/ skeletal morphogenesis is not well understood. The orphan G protein-coupled receptor Gpr161 localizes to primary cilia and functions as a negative regulator of Shh signaling by promoting Gli transcriptional repressor versus activator formation. Here, we show that forelimb buds are not formed in Gpr161 knockout mouse embryos despite establishment of prospective limb fields. Limb-specific deletion of Gpr161 resulted in prematurely expanded Shh signaling and ectopic Shh-dependent patterning defects resulting in polysyndactyly. In addition, endochondral bone formation in forearms, including formation of both trabecular bone and bone collar was prevented. Endochondral bone formation defects resulted from accumulation of proliferating round/periarticular-like chondrocytes, lack of differentiation into columnar chondrocytes, and corresponding absence of Ihh signaling. Gpr161 deficiency in craniofacial mesenchyme also prevented intramembranous bone formation in calvarium. Defects in limb patterning, endochondral and intramembranous skeletal morphogenesis were suppressed in the absence of cilia. Overall, Gpr161 promotes forelimb formation, regulates limb patterning, prevents periarticular chondrocyte proliferation and drives osteoblastogenesis in intramembranous bones in a cilium-dependent manner.
AB - The role of basal suppression of the sonic hedgehog (Shh) pathway and its interaction with Indian hedgehog (Ihh) signaling during limb/ skeletal morphogenesis is not well understood. The orphan G protein-coupled receptor Gpr161 localizes to primary cilia and functions as a negative regulator of Shh signaling by promoting Gli transcriptional repressor versus activator formation. Here, we show that forelimb buds are not formed in Gpr161 knockout mouse embryos despite establishment of prospective limb fields. Limb-specific deletion of Gpr161 resulted in prematurely expanded Shh signaling and ectopic Shh-dependent patterning defects resulting in polysyndactyly. In addition, endochondral bone formation in forearms, including formation of both trabecular bone and bone collar was prevented. Endochondral bone formation defects resulted from accumulation of proliferating round/periarticular-like chondrocytes, lack of differentiation into columnar chondrocytes, and corresponding absence of Ihh signaling. Gpr161 deficiency in craniofacial mesenchyme also prevented intramembranous bone formation in calvarium. Defects in limb patterning, endochondral and intramembranous skeletal morphogenesis were suppressed in the absence of cilia. Overall, Gpr161 promotes forelimb formation, regulates limb patterning, prevents periarticular chondrocyte proliferation and drives osteoblastogenesis in intramembranous bones in a cilium-dependent manner.
KW - Endochondral bone
KW - G protein-coupled receptor
KW - Hedgehog
KW - Intramembranous bone
KW - Limb
KW - Primary cilia
UR - http://www.scopus.com/inward/record.url?scp=85040787376&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040787376&partnerID=8YFLogxK
U2 - 10.1242/dev.154054
DO - 10.1242/dev.154054
M3 - Article
C2 - 29222391
AN - SCOPUS:85040787376
VL - 145
JO - Development (Cambridge)
JF - Development (Cambridge)
SN - 0950-1991
IS - 1
M1 - dev154054
ER -