Vertebrate Embryo: Limb Development

Tickle, Cheryll; Towers, Matthew

doi:10.1002/9780470015902.a0000728.pub3

Cited by 2 publications

(2 citation statements)

References 54 publications

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“…We propose that the proximal-distal patterning effects we observe are a result of a disruption of the temporal sequence of limb development rather than a spatial patterning effect. Limb structures develop in proximal to distal manner such that bones in the stylopod are specified and form before the zeugopod and autopod elements (Tickle and Towers, 2020). One hypothesis to account for the phenotypes we observe in Prx1-cre;Foxc1 Δ/Δ ;Foxc2 Δ/Δ embryos is the possibility that fewer skeletogenic cells are available in such mutants, either through impaired differentiation of precursor cells into chondrocytes or reduced proliferation of the progenitor population; and thus this pool of cells is exhausted or diminished as distal structures form.…”

Section: Discussionmentioning

confidence: 99%

“…In this process, a cartilaginous template is first formed by chondrocytes to grow and shape the bone before being replaced by bone-forming osteoblasts. In the limb, this event initiates as mesenchymal progenitors from the lateral plate mesoderm condenses and these cells differentiate into chondrocytes (Tickle and Towers, 2020). Once formed, chondrocytes will progress through a series of stepwise differentiation events to form a layered, organized structure known as the growth plate (Yeung .…”

Section: Introductionmentioning

confidence: 99%

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Foxc1andFoxc2function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center

Almubarak

Zhang

et al. 2023

Preprint

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The forkhead box transcription factor genes Foxc1 and Foxc2 are expressed in the condensing mesenchyme of the developing skeleton prior to the onset of chondrocyte differentiation. To determine the roles of these transcription factors in limb development we deleted both Foxc1 and Foxc2 in lateral plate mesoderm using the Prx1-cre mouse line. Resulting compound homozygous mice died shortly after birth with exencephaly, and malformations to this sternum and limb skeleton. Notably distal limb structures were preferentially affected, with the autopods displaying reduced or absent mineralization. The radius and tibia bowed and the ulna and fibula were reduced to an unmineralized rudimentary structure. Molecular analysis revealed reduced expression of Ihh leading to reduced proliferation and delayed chondrocyte hypertrophy at E14.5. At later ages, Prx1-cre;Foxc1Δ/ Δ;Foxc2 Δ / Δ embryos exhibited restored Ihh expression and an expanded COLX-positive hypertrophic chondrocyte region, indicating a delayed exit and impaired remodeling of the hypertrophic chondrocytes. Osteoblast differentiation and mineralization were disrupted at the osteochondral junction and in the primary ossification center (POC). Levels of OSTEOPONTIN were elevated in the POC of compound homozygous mutants, while expression of Phex was reduced, indicating that impaired OPN processing by PHEX may underlie the mineralization defect we observe. Together our findings suggest that Foxc1 and Foxc2 act at different stages of endochondral ossification. Initially these genes act during the onset of chondrogenesis leading to the formation of hypertrophic chondrocytes. At later stages Foxc1 and Foxc2 are required for remodeling of HC and for Phex expression required for mineralization of the POC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Foxc1andFoxc2function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center

Almubarak

Zhang

et al. 2023

Preprint

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FOXC1 and FOXC2 regulate growth plate chondrocyte maturation towards hypertrophy in the embryonic mouse limb skeleton

Almubarak,

Zhang,

Zhang

et al. 2024

Development

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The Forkhead box transcription factors Foxc1 and Foxc2 are expressed in condensing mesenchyme cells at the onset of endochondral ossification. We used the Prx1-cre mouse to ablate Foxc1 and Foxc2 in limb skeletal progenitor cells. Prx1-cre;Foxc1Δ/ Δ;Foxc2Δ/Δ limbs were shorter than controls, with worsening phenotypes in distal structures. Cartilage formation and mineralization was severely disrupted in the paws. The radius and tibia were malformed, while the fibula and ulna remained unmineralized. Chondrocyte maturation was delayed with fewer Indian Hedgehog-expressing, prehypertrophic chondrocytes forming and a smaller hypertrophic chondrocyte zone. Later, progression out of chondrocyte hypertrophy was slowed, leading to an accumulation of COLX-expressing hypertrophic chondrocyte zone and formation of a smaller primary ossification center with fewer osteoblast progenitor cells populating this region. Targeting Foxc1 and Foxc2 in hypertrophic chondrocytes with Col10a1-cre also resulted in an expanded hypertrophic chondrocyte zone and smaller primary ossification center. Our findings suggest that Foxc1 and Foxc2 direct chondrocyte maturation towards hypertrophic chondrocyte formation. At later stages, Foxc1 and Foxc2 regulate function in hypertrophic chondrocyte remodelling to allow primary ossification center formation and osteoblast recruitment.

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Vertebrate Embryo: Limb Development

Cited by 2 publications

References 54 publications

Foxc1andFoxc2function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center

Foxc1andFoxc2function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center

FOXC1 and FOXC2 regulate growth plate chondrocyte maturation towards hypertrophy in the embryonic mouse limb skeleton

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