Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds

Zúñiga, Aimée; Haramis, Anna-Pavlina G.; McMahon, Andrew P.; Zeller, Rolf

doi:10.1038/44157

Cited by 418 publications

(140 citation statements)

References 29 publications

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“…This shift is correlated with anterior expansion of the expression domain of Gli1, a transcriptional target of SHH signaling (8), and with a reduction in size of the Gli1-free anterior domain. Fgf8 expressing AER was narrower and its posterior domain was missing in Sall4 CKO hindlimb buds, which is consistent with the positive feedback loop between the ZPA and AER (29,30). Accordingly, expression of Fgf10, whose expression in developing limb buds is maintained by FGF8 signaling (26), exhibited a smaller expression domain (Fig.…”

Section: Sall4supporting

confidence: 58%

Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

Akiyama

Kawakami

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore-and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.Sall4 | Gli3 | limb progenitors | appendicular skeletal elements | Plzf-Hox H ow progenitor cells are spatially and temporarily organized to construct an organ is a central question in developmental biology. Limb skeletal elements develop from limb progenitors, which arise from the lateral plate mesoderm (LPM) that is originated from epithelial somatopleure (1). Limb progenitors initially form two paired protrusions, fore-and hindlimb buds, whose initiation occurs around embryonic day (E) 9.0 and E9.5, respectively, in mouse embryos. In the following steps, limb signaling centers, known as the zone of polarizing activity (ZPA) and apical ectodermal ridge (AER), are established. SHH (Sonic hedgehog) from the ZPA and FGF8 from the AER are major signal molecules that regulate proliferative expansion and patterning of early limb progenitor cells (reviewed in ref. 2). These processes lead to development of functional limbs with each skeletal element adopting a unique shape at a distinct location.Several studies suggest that limb progenitors consist of two distinct pools, an anterior progenitor pool and a posterior progenitor pool. The posterior progenitor pool consists of cells that once expressed Shh and cells that received paracrine effects of SHH, which contribute to digit 2 (d2), d3, d4, and d5 and the posterior zeugopod (ulna, fibula) (3-6). Contrary to this, the anterior ...

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Section: Sall4supporting

confidence: 58%

Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

Akiyama

Kawakami

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been shown that these signaling centers are interconnected, but the way they interact is not completely understood (Laufer et al, 1994;Niswander et al, 1994;Zú ñiga et al, 1999;Pizette et al, 2001). In addition, although various molecules mediating the action of the signaling centers have been identified and their signaling pathways elucidated, many components are still missing (Capdevilla and Izpisú aBelmonte, 2001).…”

Section: Introductionmentioning

confidence: 99%

Expression and regulation of eHAND during limb development

Fernandez-Teran

Piedra

Rodríguez‐Rey

et al. 2003

Developmental Dynamics

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eHAND is a bHLH transcription factor with important functions during embryogenesis. Here, we report that eHAND has a dynamic pattern of expression during limb development. In chick embryos, eHAND expression is first observed in the ventral mesoderm of the emerging limb. Its expression is then restricted to an anteroventral area of mesoderm at mid-level in the proximodistal axis. At later stages, expression is observed in the autopod encompassing the ventral tendons of the digits. In mouse embryos, only the anteroventral domain of expression is conserved, the early ventral expression not being detectable and the late pattern of expression differing clearly from that in the chick. A constant feature of all areas of expression is their ventral and anterior localization. Respecification of the anterior mesoderm as occurs secondarily to Sonic hedgehog (SHH) or retinoic acid application to the anterior border leads to downregulation of eHAND expression. Accordingly, eHAND expression is not detectable in talpid 2 mutant limbs, which are considered to be posteriorized limbs. However, eHAND expression is little modified in oligozeugodactyly, a chick mutant that lacks Shh signaling in the limb but retains certain anteroposterior polarity. Interestingly, eHAND expression is also linked to the ventral identity of the mesoderm and is repressed by the dorsal ectoderm. It is also positively regulated by bone morphogenetic protein signaling, which is also known to participate in dorsoventral patterning. We suggest that eHAND expression may be related to the anteroventral identity of the mesoderm. However, in overexpression experiments using retroviral vectors, only a low percentage of cases (5%) showed phenotypic alterations, consisting of a duplication of digit 2. Developmental Dynamics 226:690 -701, 2003.

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“…In the tetrapod limb bud, tempered activity of Bone Morphogenetic Protein (Bmp) family members by BMP antagonists is crucial in maintaining feedback between the zone of polarizing activity and the apical ectodermal ridge. BMP signaling negatively regulates limb bud outgrowth by promoting apical ectodermal ridge regression (30,31), and this effect is counteracted by Shh-dependent expression of the secreted BMP antagonist Gremlin (32,33). A similar role for antagonist-modulated BMP signaling has been demonstrated in the developing mammalian genital tubercle (34).…”

Section: Discussionmentioning

confidence: 83%

Holocephalan embryos provide evidence for gill arch appendage reduction and opercular evolution in cartilaginous fishes

Gillis

Rawlinson²,

Bell³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Chondrichthyans possess endoskeletal appendages called branchial rays that extend laterally from their hyoid and gill-bearing (branchial) arches. Branchial ray outgrowth, like tetrapod limb outgrowth, is maintained by Sonic hedgehog (Shh) signaling. In limbs, distal endoskeletal elements fail to form in the absence of normal Shh signaling, whereas shortened duration of Shh expression correlates with distal endoskeletal reduction in naturally variable populations. Chondrichthyans also exhibit natural variation with respect to branchial ray distribution-elasmobranchs (sharks and batoids) possess a series of ray-supported septa on their hyoid and gill arches, whereas holocephalans (chimaeras) possess a single hyoid arch raysupported operculum. Here we show that the elongate hyoid rays of the holocephalan Callorhinchus milii grow in association with sustained Shh expression within an opercular epithelial fold, whereas Shh is only transiently expressed in the gill arches. Coincident with this transient Shh expression, branchial ray outgrowth is initiated in C. milii but is not maintained, yielding previously unrecognized vestigial gill arch branchial rays. This is in contrast to the condition seen in sharks, where sustained Shh expression corresponds to the presence of fully formed branchial rays on the hyoid and gill arches. Considered in light of current hypotheses of chondrichthyan phylogeny, our data suggest that the holocephalan operculum evolved in concert with gill arch appendage reduction by attenuation of Shhmediated branchial ray outgrowth, and that chondrichthyan branchial rays and tetrapod limbs exhibit parallel developmental mechanisms of evolutionary reduction.

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Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds

Cited by 418 publications

References 29 publications

Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

Expression and regulation of eHAND during limb development

Holocephalan embryos provide evidence for gill arch appendage reduction and opercular evolution in cartilaginous fishes

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