Conservation of linkage and evolution of developmental function within the Tbx2/3/4/5 subfamily of T-box genes: implications for the origin of vertebrate limbs

Horton, Amy C.; Mahadevan, Navin R.; Minguillón, Carolina; Osoegawa, Kazutoyo; Rokhsar, Daniel S.; Ruvinsky, Ilya; Jong, Pieter J. de; Logan, Malcolm; Gibson‐Brown, Jeremy J.

doi:10.1007/s00427-008-0249-5

Cited by 53 publications

(59 citation statements)

References 73 publications

(70 reference statements)

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“…In transgenic analysis, constructs containing fragments of the mouse Tbx5 and Tbx4 genomic regions are able to drive gene expression in the forelimb-and hindlimbforming regions of the LPM while, in contrast, the amphiTbx4/5 genomic locus appears to lack the regulatory modules enabling expression in the LPM. In accordance with broadly accepted evolutionary models, these results suggest that changes at the level of the regulation of Tbx5 and Tbx4expression, rather than the generation of novel protein function, was necessary for the acquisition of paired appendages during vertebrate evolution (Horton et al, 2008;Minguillon et al, 2009). …”

Section: Limb Forming Capacity Of Tbx4 and Tbx5 Is Evolutionarily Ancsupporting

confidence: 85%

Regulation of limb bud initiation and limb‐type morphology

Duboc¹,

Logan²

2011

Developmental Dynamics

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While the paired forelimb and hindlimb buds of vertebrates are initially morphologically homogeneous, as the limb progenitors differentiate, each individual tissue element attains a characteristic limb-type morphology that ultimately defines the constitution of the forelimb or hindlimb. This review focuses on contemporary understanding of the regulation of limb bud initiation and formation of limb-type specific morphologies and how these regulatory mechanisms evolved in vertebrates. We also attempt to clarify the definition of the terms limb-type identity and limb-type morphology that have frequently been used interchangeably. Over the last decade, three genes, Tbx4, Tbx5, and Pitx1, have been extensively studied for their roles in limb initiation and determining limb-type morphologies. The role of Tbx4 and Tbx5 in limb initiation is clearly established. However, their putative role in the generation of limb-type morphologies remains controversial. In contrast, all evidence supports a function for Pitx1 in determination of hindlimb morphologies.

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Section: Limb Forming Capacity Of Tbx4 and Tbx5 Is Evolutionarily Ancsupporting

confidence: 85%

Regulation of limb bud initiation and limb‐type morphology

Duboc¹,

Logan²

2011

Developmental Dynamics

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“…It is suggested essential cis-regulatory elements (located in flaking or intragenic regions) are likely to be found in close vicinity to these loci. 52 Minguillon et al 53 showed that changes at the regulatory level of Tbx4 and Tbx5 expression were necessary for the development of paired appendages during vertebrate evolution, rather than the generation of novel protein function. We speculate that the atypical HOS phenotype seen in this family could be due to a number of possible underlying pathogenetic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

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Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.

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“…The full-length sequence of the AmphiTbx4/5 gene was deduced from the sequence of the CH302 78M15 BAC (17). We used RT-PCR on a 56-h embryonic cDNA sample to obtain the putative full-length coding region.…”

Section: Methodsmentioning

confidence: 99%

Tbx4/5 gene duplication and the origin of vertebrate paired appendages

Minguillón

Gibson‐Brown

Logan

2009

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

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Paired fins/limbs are one of the most successful vertebrate innovations, since they are used for numerous fundamental activities, including locomotion, feeding, and breeding. Gene duplication events generate new genes with the potential to acquire novel functions, and two rounds of genome duplication took place during vertebrate evolution. The cephalochordate amphioxus diverged from other chordates before these events and is widely used to deduce the functions of ancestral genes, present in single copy in amphioxus, compared to the functions of their duplicated vertebrate orthologues. The T-box genes Tbx5 and Tbx4 encode two closely related transcription factors that are the earliest factors required to initiate forelimb and hind limb outgrowth, respectively. Since the genetic components proposed to be responsible for acquiring a trait during evolution are likely to be involved in the formation of that same trait in living organisms, we investigated whether the duplication of an ancestral, single Tbx4/5 gene to give rise to distinct Tbx4 and Tbx5 genes has been instrumental in the acquisition of limbs during vertebrate evolution. We analyzed whether the amphioxus Tbx4/5 gene is able to initiate limb outgrowth, and assayed the amphioxus locus for the presence of limb-forming regulatory regions. We show that AmphiTbx4/5 is able to initiate limb outgrowth and, in contrast, that the genomic locus lacks the regulatory modules required for expression that would result in limb formation. We propose that changes at the level of Tbx5 and Tbx4 expression, rather than the generation of novel protein function, have been necessary for the acquisition of paired appendages during vertebrate evolution.S ince Ohno's visionary hypothesis concerning the origin of vertebrate innovations by genome duplication (1), numerous reports have been published supporting this concept (reviewed in ref.2). The cephalochordate amphioxus, a limbless extant invertebrate relative of the vertebrates (3), has been extensively used to study the ancestral functions of genes, present in single copy in amphioxus, that have been duplicated in the vertebrate lineage. Amphioxus exhibits many basal chordate characteristics, including the presence of a dorsal nerve cord, a notochord, and segmented paraxial mesoderm, but lacks many vertebrate characteristics such as migratory neural crest cells, a cranium, or an endoskeleton (4). We sought to investigate the origin of one of the most successful vertebrate innovations, paired appendages, which include the pectoral and pelvic fins of fish and their derived homologues, the forelimbs and hind limbs of tetrapods.The T-box genes Tbx4 and Tbx5 are paralogous genes that arose by duplication of a single, ancestral Tbx4/5 gene. Extant amphioxus possesses a single Tbx4/5 gene (AmphiTbx4/5) (5) and lacks paired appendages, whereas all jawed vertebrates with two pairs of paired appendages have distinct, postduplication Tbx4 and Tbx5 genes. In vertebrates, Tbx5 is expressed in the lateral plate mesoderm (LPM) of the presump...

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Conservation of linkage and evolution of developmental function within the Tbx2/3/4/5 subfamily of T-box genes: implications for the origin of vertebrate limbs

Cited by 53 publications

References 73 publications

Regulation of limb bud initiation and limb‐type morphology

Regulation of limb bud initiation and limb‐type morphology

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Tbx4/5 gene duplication and the origin of vertebrate paired appendages

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