2016 Group Project 5

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2016 Student Projects 
Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta
2016 Group Project Topic - Signaling in Development

OK you are now in a group, add a topic with your student signature to the group page.

This page is an undergraduate science embryology student project and may contain inaccuracies in either descriptions or acknowledgements.
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Mark Hill.jpg Science Student Projects
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T-box genes and their signalling

Introduction

The T-box family of transcription factors exhibits widespread involvement throughout development in all metazoans. [1] PMID 9504043

[Table needs to be inserted] Table adapted from PMID 16258075

From the limb development lecture, two major signalling pathways that involve Tbx: 1) FGF signaling (FGF10 and FGF8) 2) Wnt signaling pathway


THINGS TO STILL INCLUDE: -Where the name comes from - 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. [2] This homology domain encodes a polypeptide region that we have named the T-box.[3]

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[4]. 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[5]. 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[6]. Crystallographic determination of the structure of the DNA-binding domain, now called the Tbox, revealed a new way through which proteins recognize DNA[7].

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

(including current research)

Cardiac development

PMID 15580613 PMID 16258075 PMID 1851989

Limb Development

PMID 11782414 PMID 12490567 PMID 22872086 PMID 12736217 PMID 26212321 PMID 21932311

http://www.ncbi.nlm.nih.gov/books/NBK10003/ http://dev.biologists.org/content/130/3/623/F1

Respiratory Development

PMID 22876201 key findings: Both Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung and trachea. 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. Lung-specific Tbx4 heterozygous;Tbx5 conditional null mice die soon after birth due to respiratory distress. These pups have small lungs and show severe disruptions in tracheal/bronchial cartilage rings. Moreover, Tbx4 and Tbx5 interact with Fgf10 during the process of lung growth and branching but not during tracheal/bronchial cartilage development. Tbx in lung and trachea development.png Tbx in lung and trachea development[8]

PMID 12588840

Palate Development

PMID 22371266

Dorsalventral patterning

PMID 14737183

Abnormalities

Z5039628 (talk) 19:37, 1 September 2016 (AEST)

TBX1/DIGEORGE SYNDROME; TBX3/ULNAR-MAMMARY SYNDROME; TBX5/HOLT– ORAM SYNDROME; TBX19/ISOLATED ACTH DEFICIENCY; TBX22/CLEFT PALATE

Z5039628 (talk) 23:16, 8 September 2016 (AEST)

PMID 10235264 PMID 18505863 PMID 15066124


Holt-Oram Syndrome primary article PMID 11161571 OMIM 142900

Animal models

Marsupial forelimb development PMID 21098569

PMID 24299415

PMID 11427155

PMID 22235805

This study [9]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.

Glossary

Good places to look

PubMed Biomed Central OMIM PNAS PLOS

References

  1. <pubmed>25294936</pubmed>
  2. <pubmed>2154694</pubmed>
  3. <pubmed>792065</pubmed>
  4. <pubmed>11268043</pubmed>
  5. <pubmed>2154694</pubmed>
  6. <pubmed>8344258</pubmed>
  7. <pubmed>9349824</pubmed>
  8. <pubmed>22876201</pubmed>
  9. <pubmed>22235805</pubmed>