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|2016 Group Project Topic - Signaling in Development
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- 1 T-box genes and their signalling
- 1.1 Introduction
- 1.2 Features of the T-box family
- 1.3 Origins of the T-box genes
- 1.4 Functions of T-box in development
- 1.5 Abnormalities
- 1.6 Animal models
- 1.7 Ancient origins and evolution of the T-box gene family
- 1.8 Glossary
- 1.9 Good places to look
- 1.10 References
T-box genes and their signalling
The T-Box (TBX) genes encode for T-box proteins, a family of transcription factors with more than 20 members identified in humans so far, and homologues in many other organisms. These TBX proteins are termed transcription factors because of their ability to regulate the expression and subsequent activity of other genes by binding to DNA. T-box proteins are characterised by a DNA-binding motif known as the T-box (which is where their name is derived) that binds DNA. Many researchers have identified important roles of the TBX genes in the development of the heart and limbs. TBX genes have also found to regulate patterning and cell fate, cell survival, and/or proliferation. And so, mutations in these genes lead to human disorders including Di-George Syndrome and Holt-Oram syndrome.  PMID 9504043
What does T-Box mean?
The T-box gene and transcription factors of the T-box family play an important role in vertebrate development. The founding member of the T-box family is brachyura which comes from the greek and means short tail . This gene was discovered following experimental studies with a short tailed mouse that harboured a mutation which affected tail length and embryonic development (Dobrovolskaïa-Zavadskaïa, 1927). Brakhus means short in greek and oura meaning tail.
Nadezhda Alexandrovna Dobrovolskaya-Zavadskaya first described the brachyury mutation in 1927 as a mutation that affected tail length and sacral vertebrae in heterozygous mice .
The brachyury gene (which is also known as T) soon was studied in great detail due to its important role in the development of the notochord and posterior mesoderm. Mutations in T are shown to cause embryonic lethality in homozygote mice and short tails in heterozygote mice(Papaioannou, 2001). Now according to human and mouse genome the gene brachyura has the symbol T and gene name T, however the gene is described as brachyury.
- The family of TBox genes -Where the gene is located with respect to other genes - using Omim, where the mutation occurs
Features of the T-box family
The defining feature of the T-box gene family is a conserved domain that was first uncovered in the sequence of the mouse T locus, or Brachyury gene.  This homology domain encodes a polypeptide region that has been named the T-box.. The following table outlines the functions of some important T-box genes, including their location and associated human diseases.
Summary of the main T-box genes
|T-box gene||Main expression sites during embryogenesis||Function||Abnormalities|
|Tbx1||Pharyngeal endoderm, mesoderm core of the first pharyngeal arch, head mesoderm ventral to hindbrain, sclerotome||Pharyngeal arch arteries development, governs the transition between stem cell quiescence and proliferation in hair follicles, associated with developmental abnormalities with the ear, facial and cardiac outflow||DiGeorge syndrome, Velocardiofacial syndrome, Conotruncal anomaly face syndrome, Tetralogy of Fallot|
|Tbx2||Allantois, non-chanmber myocardium, optic and otic vesicles, naso-facial mesenchyme, limbs, lungs, genitalia||Potent immortalizing gene that acts by downregulating CDKN2A, regulates Anf expression in chamber myocardium development||None identified|
|Tbx3||Non-chamber myocardium (sinoatrial region, AV canal and interventricular ring), expressed with TBX2, TBX3, and TBX5 in the embryonic neural retina||Provides positional information important for topographic mapping in differentiation of distinct cell types across the laminar axis of the retina, development of functional ectopic pacemakers, stimulates Nanog, Tbx3 specifies digit III and the combination of Tbx2 and Tbx3 specifies digit IV, acting together with the interdigital BMP signaling cascade. The fetal lung, kidney, heart, liver, and spleen in humans expresses this gene||Ulnar-mammary syndrome|
|Tbx4||Hindlimb, mandibular and lung mesenchyme, atrium and body wall||Developmental pathways of the lower limbs and the pelvis in humans||Ischiocoxopodopatellar syndrome, Small patella syndrome|
|Tbx5||Cardiac cresent, heart tube, sinus venous, common atrium, left ventricle (LV) and right ventricle (RV) forelimb, eye||Promotes cardiomyocyte differentiation, interaction with GATA4 cause of human cardiac septal defects||Holt-Oram syndrome|
|Tbx18||Splanchnic mesoderm, septum traversum, epicardium||Maintain the separation of anterior and posterior somite compartments, specification of ureteral mesenchyme and SMC differentiation in the ureter||Congenital anomalies of kidney and urinary tract 2|
|Tbx20||Allantois, lateral plate mesoderm, cardiac crescent, heart tube, hindbrain, eye||Cardiac development and yolk sac vascular remodeling||Atrial septal defect 4|
Table adapted from: Table 1. Embryonic expression and mutant phenotypes of mouse cardiac T-box genes 
Origins of the T-box genes
The story of the T-box genes began in Paris at the Pasteur laboratory in the 1920s with the Russian scientist Nadine Dobrovolskaïa-Zavadskaïa, who embarked on a pioneering screen for X-ray-induced developmental mouse mutants. Her isolation of a mouse strain with a short tail, caused by a semidominant heterozygous mutation in a locus she called T, represented one of the first successful mammalian genetic screens, and provided one of the earliest links between gene activity and cell behaviour during embryogenesis. The mid-gestational death of homozygous T embryos, with perturbed development of the posterior mesoderm and notochord, demonstrated an essential requirement for T during gastrulation, and led to the earliest insights into the inductive influences of notochord on neural tube and somite development. Over 60 years later T, now also known as brachyury, meaning ‘short tail’ in Greek, was cloned in one of the earliest positional cloning efforts in the mouse. At the time, lack of homology in the T-gene product to any previously characterized protein gave no clues as to its biochemical role until, in 1993, it was revealed to be a novel sequence-specific DNA-binding protein. Crystallographic determination of the structure of the DNA-binding domain, now called the Tbox, revealed a new way through which proteins recognize DNA.
TO DO: Produce a timeline for the history of the TBox gene - type TBOx into PubMed and sort the findings by age - use this to see when the first journal articles where released related to TBox and limb development, how this research has improved and developed, where it is heading in the future
Functions of T-box in development
T-box genes are a growing family of transcription factors that are expressed in diverse patterns throughout vertebrate development. They have emerged as key players in embryonic patterning, tissue differentiation and morphogenesis, particularly in vertebrates and some specific examples have been described in the following sections.
The heart is one of the first organs to develop and function in vertebrate embryos. Its formation is a complex process and requires contributions from multiple transcription factors, including GATA-4, eHAND, dHAND, Irx4, and TBX genes .
In the developing heart, Tbx5 expression can be first detected at stage 12 along the entire rostrocaudal length of the fused heart tube. Although it is expressed very early in cardiac embryogenesis, Tbx5 is not essential for cardiac crescent formation or for development of the early heart tube. It is at the stage where growth of the posterior segment (atria and left ventricle) of the heart which requires Tbx5, and does not occur in embryos that lack a Tbx5. In contrast, RV and outflow tract development appears to be Tbx5 independent. It is interesting to note that the role of TBX5 in the growth and maturation of posterior heart is evolutionarily conserved from amphibia (Xenopus) to mammals.
The signalling mechanism of TBX5 involves interaction with NKX2-5 which synergistically promotes cardiomyocyte differentiation. Both these molecules bind directly to the promoter of the gene encoding cardiac-specific natriuretic peptide precursor type A (NPPA) alongside each other, and the 2 transcription factors lead to synergistic activation. Moreover, GATA4 a transcription factor essential for heart formation has been shown to interact with TBX5. A mutation of GATA4 can result in human congenital heart defects as this transcription factor is essential for functional separation of the four cardiac chambers. Therefore Tbx5 transcription factor is involved in directing gene expression in morphogenetic processes associated with specific chamber formation and any mutations can cause heart septal defects as seen in Holt–Oram syndrome (See section below on Abnormalities for further info).
Furthermore, in the secondary heart field another Tbx gene, Tbx1 has been found to function in both growth and differentiation. Fibroblast growth factors (Fgfs) 8 and 10 are key downstream effectors of Tbx1 that are expressed in secondary heart field mesoderm and associated endoderm, as well as weakly in the outflow tract. Tbx1 -> Fgf8/Fgf10 pathway in driving proliferation in secondary heart field mesoderm, contributing to OFT growth. BMP proteins are also induced in secondary heart field cells proximal to the inflow and outflow poles of the heart. BMPs can induce cardiomyogenic differentiation in collaboration with Fgf8 and can moderate the proliferation of secondary heart field mesoderm. Therefore, a delicate balance between the levels of Fgf and BMP factors appears essential for secondary heart field development.
PMID 11702954 PMID 11572777 PMID 15580613 PMID 16258075 PMID 17460765
Limb formation occurs as a result of interplay between fibroblast growth factor (FGF) and Wnt signaling. What initiates these signaling cascades and thus limb bud outgrowth at defined locations involve four members of the T-box family of transcription factors (Tbx2-Tbx5) as well as other molecules which are expressed in developing limb buds. Limb bud outgrowth is initiated and maintained by establishing a positive feedback loop of FGF signaling comprised of Fgf10 expressed in the lateral plate mesoderm (LPM), inducing the expression of Fgf8 in the overlying, distal ectoderm. Initial expression of Fgf10 in the forelimb- and hindlimb-forming LPM is controlled by Tbx transcription factors, Tbx5 in the forelimb and Tbx4 in the hindlimb, and deletion of either Tbx5 or Tbx4 causes outgrowth defects of limb buds.
The expression of Tbx4 and Tbx5, is primarily restricted to the developing hindlimbs and forelimbs, respectively. While the expression of Tbx2 and Tbx3 is present in both limbs.
Using the chick model, Tbx genes have been proven to specify posterior digit identity through Shh and BMP signaling. . In particular, Tbx2 acts upstream of Shh and BMP2, and Tbx3 regulates BMP2. Conversely, Shh and BMP4 upregulate the posterior expression of Tbx2 and Tbx3. These lines of evidence suggest that the feedback and feedforward regulation between Tbx2/3 and the Shh and BMP signaling cascades is pivotal for the specification of posterior digit identities. Furthermore, RA and Shh both induced Tbx2.
Tbx4 and Tbx5 genes are also implicated in the development of the limbs. They are first expressed in lateral plate mesoderm within clearly defined territories at the time the prospective limb fields are being specified by Homeobox (Hox) genes. Hox genes may therefore be responsible for regulating expression of these Tbox genes within the limb fields. Fgf-10 expression is also initiated in lateral plate mesoderm around this time, and FGF10 is a good candidate for the mesodermal factor that initiates limb outgrowth and signals the adjacent ectoderm to express FGF8 .
PMID 14723846 PMID 9609833 PMID 9655805 PMID 9550719 PMID 8798150 PMID 11782414 PMID 12490567 PMID 22872086 PMID 12736212 PMID 26212321 PMID 21932311
Molecular Mechanisms of Limb Bud Formation 
Close up of Tbx5 role in the Initiation of Limb Bud Formation
http://www.ncbi.nlm.nih.gov/books/NBK10003/ http://dev.biologists.org/content/130/3/623/F1 From the limb development lecture, two major signalling pathways that involve Tbx: 1) FGF signaling (FGF10 and FGF8) 2) Wnt signaling pathway
In a chicken model, all Tbx2 subfamily genes, Tbx2, Tbx3, Tbx4 and Tbx5 are expressed in the developing lung buds and trachea between stages 15–21 . In the mouse however, Tbx1 is expressed in lung epithelium at E12.5, Tbx2 and Tbx3 are expressed in lung mesenchyme at E11.5, and Tbx4 and Tbx5 are expressed in both lung and trachea mesenchyme at E12.5 and later.
In lung branching morphogenesis, Tbx4 and Tbx5 genetically interact with one another. In an article by Ripla et al. (2012), they demonstrated that both Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung and trachea. They showed that a loss of Tbx5 leads to a unilateral loss of lung bud specification and absence of tracheal specification in organ culture. Concordant with this defect, the expression of mesenchymal markers Wnt2 and Fgf10, as well as Fgf10 target genes Bmp4 and Spry2, in the epithelium is downregulated. This suggests that Fgf10 signaling pathway is activated downstream of Tbx4 and Tbx5 in the developing lung and that Fgf10 genetically interacts with Tbx4 and Tbx5. This is consistent with finding from Sakiyama et al. (2003) that found out that the Tbx4-Fgf10 system controls lung bud formation during chicken embryonic development. Tbx4 was found to trigger Fgf10 expression in the lung primordium mesoderm which then acquires an inductive capability for the initial budding morphogenesis of primary lung buds. Of significance, lung-specific Tbx4 heterozygous;Tbx5 conditional null mice died soon after birth due to respiratory distress. These pups have small lungs and show severe disruptions in tracheal/bronchial cartilage rings, highlighting the important role of Tbx4 and Tbx5 in respiratory development.
Tbx in lung and trachea development
Other developmental events
TBX signalling also involved in palate development. In humans, TBX1 mutation is responsible for the major phenotypes of 22q11.2 deletion syndrome (Velo-cardio-facial/DiGeorge syndrome, discussed in Abnormalities section) as well as non-syndromic submucous cleft palate, suggesting that Tbx1 is a regulator of palatogenesis. A study by Funato et al. (2012) revealed that Tbx1 regulates oral epithelial adhesion and palatal development and showed that Tbx1 -/- mice exhibit various forms of cleft palate phenotypes, including submucosal cleft palate and soft palate cleft.
Dorsoventral Patterning of the Mouse Coat by Tbx15 PMID 14737183 Palate Development PMID 22371266
Tbx6 interacting with Ripply for the formation of somite boundaries (in zebrafish) PMID 25725067 Tbx6 is required for the expression of mesp-b and ripply1 in the paraxial mesoderm during somite formation, and for the specification of the central Pax3+/Pax7+ dermomyotome. Mesp-b is necessary and sufficient for central dermomyotome formation, it inhibits myogenic differentiation and promotes dermomyotome development. Ripply1 function is required for maturation and fast muscle fiber differentiation.
Results show that Tbx6 protein has to be removed for the expression of pax3/7 and myoD in the lateral paraxial mesoderm, indicating that Tbx6 and/or Tbx6-dependent genes inhibit maturation of myogenic cells. Downstream of Tbx6, Mesp-ba promotes dermomyotome development.
A number of human disorders have been linked to mutations in T-box genes, confirming their medical importance. They include Holt– Oram syndrome/TBX5, Ulnar-Mammary syndrome/TBX3, and more recently DiGeorge syndrome/TBX1, ACTH deficiency/TBX19 and cleft palate with ankyloglossia/TBX22.
TBX1/DIGEORGE SYNDROME; The TBX1 gene can be mapped on chromosome 21 within the DiGeorge syndrome region. Vitelli et all (2003) studied mice, showing that the TBX1 gene is haploinsufficient. This means that while although mice are diploid organisms, only one functional copy of the gene exists, while the other copy has undergone a mutation, making it inactivated. This single gene is unable to produce sufficient amounts of the protein needed for TBX1 to carry out its function- the development of pouches and pharyngeal arches in these mice. In this study of mice, a deficiency of the TBx1 gene resulted in heart defects, hence suggesting the close association between the TBx1 gene and cardiovascular development.
In this study, a mouse model was used where the relevant region on chromosome 16 of the mice species, corresponding to chromosome 22q11.2, or del22q11, in humans, was deleted. These 'mutated' mice exhibited a range of cardiovascular abnormalities and defects, as well as behavioural changes. They also revealed incomplete or mutated pharangeal arch and pouch development. Tbx 1 (7-9) was identified as the gene responsible for these cardiovascular malformations. The normal development of the cochlear and vestibular organs was also observed in these mice. Thus, Tbx1 was also identified as crucial for the development of otic epithelial cells, which then later contribute to the development of these inner ear organs. These defects are also exhibited in the birth defects in humans, hence making this mouse model highly effective and suitable.
PMID 11971873 https://omim.org/entry/602054
TBX3/ULNAR-MAMMARY SYNDROME; Mutations of the TBX3 gene leads to ulnar-mammary syndrome, caused by a reduce in the levels of the functional proteins needed for normal development of limbs, mammary glands and other structures. Like DiGeorge Syndrome, this syndrome is a result of the haploinsufficiency of TBX3. This disorder is expressed in abnormalities of the limbs, teeth, genitals and mammary glands. Again, animal models of mice have shown abnormalities in mammary glands, limbs and genitalia, often dying before birth. These abnormalities are often characterised by short, stunted growth of the hindlimbs of mice, as well as missing elements to the forelimb.
On the other hand, when this gene is abundant and over-expressed, cancers in the breast, liver and skin have been seen to develop, as high levels of this gene assist in the development of tumours. Lung cancers, breast cancers, ovarian cancers, bladder cancers and liver tumours have been shown to have high levels of the TBX3 gene.
TBX5/HOLT– ORAM SYNDROME;
Mutations of the TBX5 gene has been shown to cause defects in cardiac septation and the production of isomers in humans affected with holt-oran syndrome. The TBX5 gene is mutated in affected individuals, on chromosome 12q24. Holt-Oram syndrome is an autosomal-dominant disorder, and in humans, is expressed by deformities of the upper limb, the shoulder girdle as well as defects in the septa of the heart. Animal models such as chicks have been used, where the overexpression of this gene in chicken embryos has resulted in incomplete growth of the myocardium and the trabeculae and septa of the heart. In humans, the overexpression and mutation of this gene has also been shown to inhibit normal cardiac development. This is because TBX5 is responsible for the normal proliferation of cells during cardiac development. Thumb anomaly is another expression of holt-oran syndrome, where the thumb may be completely absent, or may develop as another finger-like digit, not different from the other digits of the finger. Other indicators of this disease are heart and skeletal lesions, patent ductus arteriosus (PDA), malformation of the ventricles in the heart, mitral valve prolapse and superior vena cava anomaly.
PMID 11161571 PMID 17534187 OMIM 142900
TBX19/ISOLATED ACTH DEFICIENCY; The TBx19 gene initiates the transcription process of the Proopiomelanocortin (POMC) gene. This gene contains the instructions for the synthesis of the proopiomelanocortin protein. This protein is further transformed into smaller peptides which bind to proteins in the body, initiating various signalling pathways throughout the body. When this gene is mutated, congenital isolated adrenocorticotropic hormone deficiency develops, caused by the reduction of the secretion of Isolated adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. This is because ACTH-producing cells of the pituitary gland are damaged and cannot secrete sufficient amounts of adrenocorticotropic hormone. This results in severe hypoglycaemia and seizures in neonates. Cholestatic Liver disease also arises from this mutation, blocking or reducing the normal flow of bile through the liver. This disease has also been seen to cause a range of other clinical symptoms, including urinary incontinence, gait disturbance and dementia in older patients. Ventricular enlargement in the brain, loss of appetite and vomiting are other symptoms associated with isolated ACTH deficiency. The main treatment for this disease is hormone replacement therapy.
TBX22/CLEFT PALATE Studies on mice with cleft palate have shown that the mutations of the gene encoding TBX22, causing the gene to no longer function. Tbx22 is involved in the development of the intramembranous bone formation of the posterior hard palate, rather than palate closure, and hence a mutation of this gene results in cleft palate. These mutations of the TBX22 gene included frame shifts of the gene, splices, nonsense and missense changes to the gene sequence. TBX22 is regulated by the Mn1 transcription factor, working together to achieve normal palate development. Mutations of Tbx1 and Tbx10 are also responsible for cleft palate. The mutation of this gene also causes ankyloglossia, the development of a short and thick lingual frenulum under the tongue, limiting tongue movement. This can be corrected by surgery. Choanal atresia, a blockage of the nasal airway, was also seen in affected mice. Other developmental mutations can be seen in the incomplete formation of the vomer bone in the skull.
PMCID: PMC2758147 PMCID: PMC2586179 PMCID: PMC2227921 http://www.mayoclinic.org/diseases-conditions/tongue-tie/basics/definition/con-20035410 https://medlineplus.gov/ency/article/001642.htm
PMID 10235264 PMID 18505863 PMID 15066124
The gene brachyury is important in all bilateral organisms (vertebrates- chordates and invertebrates such as mollusca). The brachyury gene is believed to have a conserved role in defining the midline of a bilateral organism  and are also fundamental in the establishment of the anterior-posterior axis 
It is thought to play a role in the development of organisms in the Phylum Cnidaria, appears to be in defining the blastopore during early development. It is also important during gastrulation where it defines the mesoderm  and experiments using tissue culture have demonstrated that the gene brachyury is also important in controlling the velocity of cells as they leave the primitive streak. 
Another important role that Brachyury has also been shown to have is to help establish the cervical vertebral blueprint during (human) fetal development. In mammals the number of cervical vertebrae is highly conserved; however a spontaneous vertebral and spinal dysplasia (VSD) mutation in this gene has been associated with the development of six or fewer cervical vertebrae instead of the usual seven. 
The T-box gene family have been identified in organisms ranging from hydra to humans and due to extensive research by many investigators , we now know that T-box is important in metazoan development including transcriptional activity, genetic targets, developmental regulatory functions, and associated disease mechanisms (reviewed in Papaioannou, 2001).
Organisms used in animal models for T-Box
Animal model studies have been performed in a number of organisms including: Drosophila (the fruit fly), Xenopus (a genus of aquatic clawed frog native to sub-Saharan Africa) zebrafish, avians, and mice. These different animals are used to examine T-box gene regulation in the developmental and disease process (reviewed in Naiche et al., 2005).
T-box genes are involved in the development and patterning of many organ systems and embryonic structures including the heart, limb, eye, central axis, and face. In addition, T-box genes are subject to regulation by or induce the expression of developmentally important signaling molecules, such as retinoic acid (RA), bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), and Wnts, in different organ systems (reviewed in Naiche et al., 2005). T-box proteins can act as transcriptional activators or repressors with a variety of cofactors to regulate expression of genes involved in cell lineage determination, differentiation, and maturation (reviewed in Tada and Smith, 2001). Overall, T-box genes are integrated into regulatory networks that control patterning, growth, and maturation of many cell types and tissues in the developing embryo.
This figure is modified from Papaioannou (2014) and shows the subfamilies or classes of genes that have been identified in the different animal groups that are indicated in green in the boxes. What can be demonstrated is that there has been a remarkable conservation of transcription factors between lineages that have been evolving independently since the last common ancestor to metazoans, and many of the T-box gene families have their origin at the base of the tree. However, diversification at the onset of metazoan evolution is evident. T, which is the most ancient T-box gene, is represented in unicellular organisms, as is Tbx7/8, a class not present in Bilateria. Sponges have a diverse set of T-box genes including several that have not been retained in Bilateria, whereas Tbx6 subfamily genes apparently arose in Bilateria. Note that this diagram represents one possible order of divergence of phyla.
Marsupial forelimb development
This study published in 2012 is the first which describes the HOX gene expression in a marsupial (Tammar wallaby Macropus eugenii) and how these genes are also responsible for limb and digit formation.
The genes responsible for digit patterning are the HOXA13 and HOXD13 which are also present and highly conserved in other vertebrates such as the chicken and the mouse.
In the tammar wallaby the forelimbs develop much faster than the hind limbs.
In the tammar wallaby the hindlimb autopod has only four digits and the fourth digit is greatly elongated while the digits two and three are syndactylous.
The authors found that the differences in the gene structure in the tammar and the changes in the expression and timing may be driving the difference in the development of the syndactylous hind limb. They suggest that the polyserine region may be responsible for marsupial syndactyly. This also needs to be studied in other marsupials with syndactyl hind limbs such as bandicoots and bibles (Peramelemorphia).
Our findings support the hypothesis that changes to the structure and function of HOXA13 and HOXD13 affect regulation of digit identity in this marsupial.
Ancient origins and evolution of the T-box gene family
T-box gene family is ancient in origin and it is thought to be found in all metazoans  . Due to the increasing availability of sequenced genomes from a diverse group of animal taxa we now know that the origin of the T-box family has been pushed back to unicellular organisms and fungi, in which one or two T-box genes, including T, have been identified .
With the analysis of the genomes of bilaterian organisms and representatives of the different phyla, four basal metazoan phyla indicate that T is the most ancient member of the T-box family and that the family has expanded throughout metazoan evolution.  In Metazoan evolution it seems that genes were added progressively one by one by gene or genome duplication and some of these genes were lost and gained in specific lineages . In present day or extant vertebrates we now know that the T-box family has radiated throughout the vast vertebrate linages and can be grouped into five subfamilies T, Tbx1, Tbx2, Tbx6 and Tbr1 . In the common ancestor of vertebrates and sponges, four of these five subfamilies were already present .
Brachyury expression in 7.5dpc CD1 mouse embryos
Good places to look
PubMed Biomed Central OMIM PNAS PLOS
|Classification||Name of organism||T-box||Usage and examples|
- <pubmed>25294936 2154694</pubmed>
- Dobrovolskaïa-Zavadskaïa, N. (1927). Sur la mortification spontanée de la queue che la souris nouveau-née et sur l'existence d'un caractère (facteur) héréditaire “non viable”. C. R. Seanc. Soc. Biol. 97, 114-116.