Localized vascular regression during limb morphogenesis in the chicken embryo. I. Spatial and temporal changes in the vascular pattern

Feinberg, Richard N.; Latker, Carole H.; Beebe, David C.

doi:10.1002/ar.1092140411

Cited by 45 publications

(25 citation statements)

References 15 publications

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“…1A) (Feinberg et al, 1986;Hallmann et al, 1987). In order to examine whether the absence of vasculature at the condensation sites forces the condensed mesenchymal cells to differentiate under hypoxic conditions we used hypoxyprobe, a molecular marker that detects hypoxic cells (Arteel et al, 1998).…”

Section: Condensed Mesenchymal Cells In the Limb Are Hypoxic And Exprmentioning

confidence: 99%

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HIF1α regulation ofSox9is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis

et al. 2007

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During early stages of limb development, the vasculature is subjected to extensive remodeling that leaves the prechondrogenic condensation avascular and, as we demonstrate hereafter, hypoxic. Numerous studies on a variety of cell types have reported that hypoxia has an inhibitory effect on cell differentiation. In order to investigate the mechanism that supports chondrocyte differentiation under hypoxic conditions, we inactivated the transcription factor hypoxia-inducible factor 1␣ (HIF1␣) in mouse limb bud mesenchyme. Developmental analysis of Hif1␣-depleted limbs revealed abnormal cartilage and joint formation in the autopod, suggesting that HIF1␣ is part of a mechanism that regulates the differentiation of hypoxic prechondrogenic cells. Dramatically reduced cartilage formation in Hif1␣-depleted micromass culture cells under hypoxia provided further support for the regulatory role of HIF1␣ in chondrogenesis. Reduced expression of Sox9, a key regulator of chondrocyte differentiation, followed by reduction of Sox6, collagen type II and aggrecan in Hif1␣-depleted limbs raised the possibility that HIF1␣ regulation of Sox9 is necessary under hypoxic conditions for differentiation of prechondrogenic cells to chondrocytes. To study this possibility, we targeted Hif1␣ expression in micromass cultures. Under hypoxic conditions, Sox9 expression was increased twofold relative to its expression in normoxic condition; this increment was lost in the Hif1␣-depleted cells. Chromatin immunoprecipitation demonstrated direct binding of HIF1␣ to the Sox9 promoter, thus supporting direct regulation of HIF1␣ on Sox9 expression. This work establishes for the first time HIF1␣ as a key component in the genetic program that regulates chondrogenesis by regulating Sox9 expression in hypoxic prechondrogenic cells.

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Section: Condensed Mesenchymal Cells In the Limb Are Hypoxic And Exprmentioning

confidence: 99%

“…During the initial stages of this process, the limb vasculature undergoes a remodeling process that renders the condensing mesenchyme avascularized (Feinberg et al, 1986;Hallmann et al, 1987). As the condensations increase in size, cells differentiate into chondrocytes, forming a cartilaginous template of the future bones.…”

Section: Introductionmentioning

confidence: 99%

HIF1α regulation ofSox9is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis

et al. 2007

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“…Between E10.5 and E12.5, the primary vascular plexus undergoes extensive patterning. Blood vessels regress from areas of emerging cartilage anlagen and rearrange into a highly branched and rich network, which is segregated from the condensation areas (Feinberg et al, 1986;Hall and Miyake, 1992;Seichert and Rychter, 1972). Previously, we showed that the condensing mesenchyme serves as a signaling center for the limb vasculature.…”

Section: Introductionmentioning

confidence: 99%

Vascular patterning regulates interdigital cell death by a ROS-mediated mechanism

Eshkar-Oren

Krief

Ferrara³

et al. 2015

Development

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Blood vessels serve as key regulators of organogenesis by providing oxygen, nutrients and molecular signals. During limb development, programmed cell death (PCD) contributes to separation of the digits. Interestingly, prior to the onset of PCD, the autopod vasculature undergoes extensive patterning that results in high interdigital vascularity. Here, we show that in mice, the limb vasculature positively regulates interdigital PCD. In vivo, reduction in interdigital vessel number inhibited PCD, resulting in syndactyly, whereas an increment in vessel number and distribution resulted in elevation and expansion of PCD. Production of reactive oxygen species (ROS), toxic compounds that have been implicated in PCD, also depended on interdigital vascular patterning. Finally, ex vivo incubation of limbs in gradually decreasing oxygen levels led to a correlated reduction in both ROS production and interdigital PCD. The results support a role for oxygen in these processes and provide a mechanistic explanation for the counterintuitive positive role of the vasculature in PCD. In conclusion, we suggest a new role for vascular patterning during limb development in regulating interdigital PCD by ROS production. More broadly, we propose a double safety mechanism that restricts PCD to interdigital areas, as the genetic program of PCD provides the first layer and vascular patterning serves as the second.

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“…Most prominently, avascularized areas emerge from previously vascularized regions as a result of vessel regression from the emerging cartilage anlage. Concurrently, the surrounding vasculature undergoes an extensive morphogenesis, forming a stereotypical, highly branched and enriched network (Feinberg et al, 1986;Hall and Miyake, 1992;Seichert and Rychter, 1972a). The mesenchymal cells that occupy these avascular areas aggregate and form high cell density condensations that will eventually differentiate into chondrocytes, thus forming cartilage models of the future bones (Hall and Miyake, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Some of these studies addressed the obvious issue of which system is patterned first, assuming that the first system to be patterned may regulate the patterning of the other tissue (Feinberg et al, 1986;Hallmann et al, 1987;Wilson, 1986). Other studies concentrated on the influence of an abnormal vasculature on limb skeleton formation and the mechanism that underlies such an effect (Caplan and Koutroupas, 1973;Feinberg and Saunders, 1982;Fraser and Travill, 1978;Hootnick et al, 1980;Jargiello and Caplan, 1983).…”

Section: Introductionmentioning

confidence: 99%

The forming limb skeleton serves as a signaling center for limb vasculature patterning via regulation ofVegf

et al. 2009

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Limb development constitutes a central model for the study of tissue and organ patterning; yet, the mechanisms that regulate the patterning of limb vasculature have been left understudied. Vascular patterning in the forming limb is tightly regulated in order to ensure sufficient gas exchange and nutrient supply to the developing organ. Once skeletogenesis is initiated, limb vasculature undergoes two seemingly opposing processes: vessel regression from regions that undergo mesenchymal condensation; and vessel morphogenesis. During the latter, vessels that surround the condensations undergo an extensive rearrangement, forming a stereotypical enriched network that is segregated from the skeleton. In this study, we provide evidence for the centrality of the condensing mesenchyme of the forming skeleton in regulating limb vascular patterning. Both Vegf loss-and gain-of-function experiments in limb bud mesenchyme firmly established VEGF as the signal by which the condensing mesenchyme regulates the vasculature. Normal vasculature observed in limbs where VEGF receptors Flt1, Flk1, Nrp1 and Nrp2 were blocked in limb bud mesenchyme suggested that VEGF, which is secreted by the condensing mesenchyme, regulates limb vasculature via a direct longrange mechanism. Finally, we provide evidence for the involvement of SOX9 in the regulation of Vegf expression in the condensing mesenchyme. This study establishes Vegf expression in the condensing mesenchyme as the mechanism by which the skeleton patterns limb vasculature.

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Localized vascular regression during limb morphogenesis in the chicken embryo. I. Spatial and temporal changes in the vascular pattern

Cited by 45 publications

References 15 publications

HIF1α regulation ofSox9is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis

HIF1α regulation ofSox9is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis

Vascular patterning regulates interdigital cell death by a ROS-mediated mechanism

The forming limb skeleton serves as a signaling center for limb vasculature patterning via regulation ofVegf

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