Difference between revisions of "2017 Group Project 3"

From Embryology
(Developmental Signalling Processes)
(Developmental Signalling Processes)
Line 101: Line 101:
 
===Transforming growth factor-β===
 
===Transforming growth factor-β===
 
Transforming growth factor-β superfamily involves a large number of growth factors that are structurally related. These growth factors, including Nodal or its mimic Activin, bone morphogenic protein (BMP) and growth and differentiation factors, signal through SMAD-dependent and SMAD-independent pathways <pubmed>18290874</pubmed>.  
 
Transforming growth factor-β superfamily involves a large number of growth factors that are structurally related. These growth factors, including Nodal or its mimic Activin, bone morphogenic protein (BMP) and growth and differentiation factors, signal through SMAD-dependent and SMAD-independent pathways <pubmed>18290874</pubmed>.  
Nodal and its mimic Activin act through SMAD-2 and -3 to activate transcription. During embryo development, epiblast cells produce high levels of Nodal growth factors leading to a gradient of nodal in these cells. This gradient is important for mesoderm patterning (left-right asymmetric heart development) and lineage specification. For this reason, this gradient is maintained by Nodal antagonist secreted from the anterior visceral endoderm or by BMP-4 and Wnt-3 feedback loop in the extraembryonic tissues (Fig.3) <pubmed>25813860</pubmed>. Nodal/Activin’s important role in heart formation is demonstrated by animal models. Presence of Activin in amphibian embryo lead to activation of heart formation whereas the absence of Nodal co-receptor in, called Cripto, in mouse embryo resulted in failure of ES cells differentiation into cardiomyocytes <pubmed>20830688</pubmed>. Also, knocking out copies of SMAD-2 alone or both SMAD-2 ND -3 result in inappropriate specification of axial mesoderm <pubmed>12842913</pubmed>.
+
Nodal and its mimic Activin act through SMAD-2 and -3 to activate transcription. During embryo development, epiblast cells produce high levels of Nodal growth factors leading to a gradient of nodal in these cells. This gradient is important for mesoderm patterning (left-right asymmetric heart development) and lineage specification. For this reason, this gradient is maintained by Nodal antagonist secreted from the anterior visceral endoderm or by BMP-4 and Wnt-3 feedback loop in the extraembryonic tissues (Fig.3) <pubmed>25813860</pubmed>.
 +
Nodal/Activin’s important role in heart formation is demonstrated by animal models. Presence of Activin in amphibian embryo lead to activation of heart formation whereas the absence of Nodal co-receptor in, called Cripto, in mouse embryo resulted in failure of ES cells differentiation into cardiomyocytes <pubmed>20830688</pubmed>. Also, knocking out copies of SMAD-2 alone or both SMAD-2 ND -3 result in inappropriate specification of axial mesoderm <pubmed>12842913</pubmed>.
  
 +
{{File:Regulation of Nodal-Activin signalling during heart development.jpg}} <pubmed>25813860</pubmed>.
 
===FGF signalling===
 
===FGF signalling===
  

Revision as of 15:59, 28 September 2017

2017 Student Projects 
Student Projects: 1 Cerebral Cortex | 2 Kidney | 3 Heart | 4 Eye | 5 Lung | 6 Cerebellum
Student Page - here is the sample page I demonstrated with in the first labs.I remind all students that you have your own Group Forum on Moodle for your discussions, it is only accessible by members of your group.
Editing Links: Editing Basics | Images | Tables | Referencing | Journal Searches | Copyright | Font Colours | Virtual Slide Permalink | My Preferences | One Page Wiki Card | Printing | Movies | Language Translation | Student Movies | Using OpenOffice | Internet Browsers | Moodle | Navigation/Contribution | Term Link | Short URLs | 2018 Test Student

Help:Copyright Tutorial Help:Editing Basics

Marking Criteria .png

Heart

Mark Hill (talk) 16:06, 14 September 2017 (AEST) OK Feedback

  • This is very early stage of content development. Of all the possible topics this is definitely the MOST researched topic to date. You have this week to make significant progress on this page.
  • Where is the timeline of development.
  • Where is the timeline of key discoveries
  • Splanchnic mesoderm and neural crest contribution
  • Differentiation of different cardiac cell types
  • Cardiac conduction system development
  • Cardiomyocyte differentiation/function
  • Cardiac stem cells

Introduction

The cardiovascular system is the first system to develop and function in the human embryo. The rapid cardiac development is essential as the growing embryo can no longer receive oxygen and essential nutrients via diffusion alone, hence a circulatory system and a contractile heart mechanism is required to supply the embryo. We recognise the hearts normal development is vital for foetal life, and hence we have chosen to document the development of the heart from gastrulation to birth. Any defects occurring during the developmental processes can lead to congenital heart abnormalities. However, early cardiac development is a multifaceted procedure and is associated with other developmental processes such as: embryonic folding, coelom formation, and vascular development [1].

Through researching the advances in technology, coupled with the biological use of suitable animal models [2] our understanding of embryological cardiac development has evolved, and we are piecing together the mechanism underlying this development. This page will outline the importance of how heart abnormalities arise, the treatments available and the possible treatments to be developed in the future. Due to the major knowledge gaps in current embryological heart research, we acknowledge that this will impact our assignment, and aim to address further research concepts that will improve our understanding.

<pubmed> PMC1767747</pubmed>


Z5076019 (talk)

Developmental Origin

Development of Trilaminar Embryonic Disc .png


In the developing embryo the lateral plate mesoderm splits into somatic and splanchnic layers, the latter is comprised of cardiac progenitor cells [3]. The somatic mesoderm lines the ectoderm, the splanchnic mesoderm lines the endoderm, and in between lies an embryonic coelom [4] . At the end of week three, the heart develops from splanchnic mesoderm of the cardiogenic region of the embryonic plate. At the cranial end of the embryo, anterior to the developing neural tube is the initial origin of heart formation.

Morphology of Heart Tube Formation- Student Image .png

Originally, as seen in figure 2 the cardiogenic region forms laterally of the paraxial mesoderm and primitive streak of the embryonic disc. Due to the natural mesenchymal cell organisation of the mesoderm, cells ‘migrate’ and fuse at the midline of the cranial end of the embryo forming the cardiac crescent just prior cardiac tube formation and folding. As in figure 2, endoderm surrounding the primitive gut contracts, and brings the cardiogenic precursor regions of the splanchnic region towards the midline. At this time, early heart formation occurs in the form of angioblastic cords of the splanchnic mesoderm. The angioblastic cords develop into separate endochondral heart tubes moving closer together as the foregut pinches together and the yolk sac contracts into the embryo. Fusion of the two heart tubes is facilitated by apoptosis [5] . The origin of the primitive heart is in the early pericardial coelom, which is later developed into the pericardial cavity, through fusion of the pleuropericardial folds to separate the pleural cavities at the later development of the lungs (see figure 4) [6].


Heart Tube Fusion Model of Early Development.png Pericardial Development 4-6 Gestation weeks .jpg


<pubmed>PMC2691808</pubmed>

<pubmed>PMC4374196</pubmed>


[7] <pubmed>PMC1767747</pubmed> [8] <pubmed> PMC2691808 </pubmed>

Z5076019 (talk) 14:19, 26 August 2017

Developmental Timeline

Embryonic Developmental Timeline

Primary Heart Field and Heart Tube Formation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767747/

Secondary Heart Field and Cardiac Looping

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767747/

Cardiac Neural crest and Outflow tract

Atrial and Ventricular Septation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767797/

Proepicardium and Coronary Heart Development

MAIN ARTICLE --> http://www.springer.com/cda/content/document/cda_downloaddocument/9781588294432-c2.pdf?SGWID=0-0-45-387660-p173728389 http://www.nature.com/pr/journal/v57/n2/full/pr200525a.html?foxtrotcallback=true



Historic Developmental Timeline

[9]

[10]

z5178463

Developmental Signalling Processes

Heart development is a very complicated and dynamic process that requires a high degree of control and regulation. This control is achieved by several temporally regulated signalling cascade (Fig. 1) expressed at different stages of heart development.


Signalling pathways in heart development.png [1]

Wnt signalling

According to the primary mode of action, Wnt signalling pathways have been divided into two major classes, canonical and non-canonical Wnt signalling pathways. Both the pathways have a role in different stages of cardiac development which could be overlapping or independent of each other. The canonical Wnt signalling pathway involves β-catenin and is activated by a number of ligands such as Wnt-1, Wnt-2, Wnt-3A, Wnt-8A, Wnt-8B, Wnt-8C, Wnt-10A, and Wnt-10B. However, the non-canonical signalling pathway is associated with planar cell polarity and Wnt/Ca2+ pathways that are activated by different ligands such as Wnt4, Wnt5A, Wnt5B, Wnt6, Wnt7A, Wnt7B, and Wnt11 [2].

Canonical/β -catenin signaling is essential for mesoderm formation. Upon binding of the Wnt ligands to the Frizzled receptor, a seven-transmembrane receptor, or the co-receptor LRP-5/6, the Canonical signaling pathway is activated. This leads to cytoplasmic accumulation of β -catenin in one side of the embryo and its translocation to the nucleus where it drives the activation of transcription factors required to determine the site at which mesoderm and endoderm formation will occur in the embryo. Animal studies have shown that the lack of nuclear accumulation of β -catenin results in inability of axis formation and mesoderm development whereas overexpression of β -catenin leads to the formation of secondary axis and ectopic expression of mesoderm signals. Also, homozygous deletion of β -catenin in mouse models results in absence of primitive streak and mesoderm formation [3].

Once mesoderm formation proceeds, the β -catenin signal must be shut down by inhibiting factors otherwise cardiac mesoderm formation will be stopped. This indicates that canonical signaling act as a switch that either induces or suppresses cardiac development. One of the inhibiting factors include dickkopf-1(DKK1) which is an extracellular Wnt inhibitor promotes the expression of cardiac-inducing factor in the endoderm such as Hex. The latter activates paracrine factors to direct adjoining cells towards cardiac fate [4].

Wnt signalling pathways.png <pubmed>20830688</pubmed>

Transforming growth factor-β

Transforming growth factor-β superfamily involves a large number of growth factors that are structurally related. These growth factors, including Nodal or its mimic Activin, bone morphogenic protein (BMP) and growth and differentiation factors, signal through SMAD-dependent and SMAD-independent pathways <pubmed>18290874</pubmed>. Nodal and its mimic Activin act through SMAD-2 and -3 to activate transcription. During embryo development, epiblast cells produce high levels of Nodal growth factors leading to a gradient of nodal in these cells. This gradient is important for mesoderm patterning (left-right asymmetric heart development) and lineage specification. For this reason, this gradient is maintained by Nodal antagonist secreted from the anterior visceral endoderm or by BMP-4 and Wnt-3 feedback loop in the extraembryonic tissues (Fig.3) <pubmed>25813860</pubmed>. Nodal/Activin’s important role in heart formation is demonstrated by animal models. Presence of Activin in amphibian embryo lead to activation of heart formation whereas the absence of Nodal co-receptor in, called Cripto, in mouse embryo resulted in failure of ES cells differentiation into cardiomyocytes <pubmed>20830688</pubmed>. Also, knocking out copies of SMAD-2 alone or both SMAD-2 ND -3 result in inappropriate specification of axial mesoderm <pubmed>12842913</pubmed>.

File:Regulation of Nodal-Activin signalling during heart development.jpg <pubmed>25813860</pubmed>.

FGF signalling

The Notch pathway

Sonic Hedgehog

Retinoic Acid

[11]

[12]

[13]

Z5076466

Current Research And Findings

  • all

[| Effect of maternal position on fetal behavioural state and heart rate variability in healthy late gestation pregnancy]

[| Acidic fibroblast growth factor and heart development. Role in myocyte proliferation and capillary angiogenesis]

[|The Role of Na+/Ca2+ Exchanger 1 in Maintaining Ductus Arteriosus Patency]


Z5018962 (talk)z5018962Z5018962 (talk)

Animal Models

z5076466

Abnormal Development

Ventricular Septal Defect

[14]

[15] - ventricular septal defect (Penny and Vick)

Atrial Septal Defect

[16] - atrial septal defects (Giva, Martins & Wald)

Atrioventricular Septal Defect

Misc. References

[17]

[18]


z5059996

Future Questions

Z5076466

Glossary of Terms

  • all

References

  • all
  • <pubmed>12781678</pubmed>
  • <pubmed>25813860</pubmed>
  • <pubmed>16860783</pubmed>
  • <pubmed>4533091</pubmed>