Download Susana Lopes, PhD Institution: CEDOC

Project Title: Uncoupling heart and liver laterality during embryogenesis
Supervisor: Susana Lopes, PhD
Institution: CEDOC - FCM
Webpage: http://cedoc.unl.pt/cilia-regulation-and-disease/
Contact: [email protected]
Location of research lab/research center: Cilia Regulation and Disease lab
CEDOC - Centro de Estudos de Doenças Crónicas
NOVA Medical School / Faculdade de Ciências Médicas, Universidade Nova de
Lisboa
Edifício CEDOC I, Rua do Instituto Bacteriológico nº 5,5-A e 5-B, 1150-190 Lisboa
Summary:
This project sets out to investigate the role of time in the left-right organizer (LRO).
This transient embryonic organ is crucial for determining the left-right identity of the
vertebrate body-plan. Inside this organ there are exciting biophysical mechanisms of
development to be investigated. Namely, biophysical fluid flow forces that will be
translated into gene expression and determine the location of the heart on the left
and the liver on the right side of the midline axis. Such fluid flow is directional and
known to be generated by motile cilia. This flow starts by being very mild, later
becoming strong and directional due to cell shape changes. As a consequence,
during the lifetime of the LRO there is a fluid flow independent and a fluid flow
dependent time-window. We propose that this time-code of flow is crucial for LR
patterning of the internal organs. We reason that when these two time-windows get
desynchronized a condition known as heterotaxy arises. Heterotaxy presents an
uncoupling of the heart location compared to the gut and vice-versa. The molecular
mechanism behind the uncoupling of heart, gut and brain laterality is unknown and is
a fundamental developmental question that remains unsolved.
Bibliographic references:
Sampaio, P. et al. Left-Right Organizer Flow Dynamics: How Much Cilia Activity
Reliably Yields Laterality? Developmental Cell (2014).
Babu, D. & Roy, S. Left-right asymmetry: cilia stir up new surprises in the node.
Open Biology 3, 130052–130052 (2013).
Essner, J. J. et al. Kupffer's vesicle is a ciliated organ of asymmetry in the zebrafish
embryo that initiates left-right development of the brain, heart and gut. Development
132, 1247–1260 (2005).
McGrath, J. Cilia are at the heart of vertebrate left–right asymmetry. Current Opinion
in Genetics & Development 13, 385–392 (2003).
Sun, T. et al. Early asymmetry of gene transcription in embryonic human left and
right cerebral cortex. 308, 1794–1798 (2005).
Schweickert, A. et al. The nodal inhibitor Coco is a critical target of leftward flow in
Xenopus. Curr. Biol. 20, 738–743 (2010).
Lin, X. & Xu, X. Distinct functions of Wnt/ -catenin signaling in KV development and
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cardiac asymmetry. Development 136, 207–217 (2008).
Hamada, H. & Tam, P. P. L. Mechanisms of left-right asymmetry and patterning:
driver, mediator and responder. F1000Prime Rep (2014). doi:10.12703/P6-110
Norris, D. P. Cilia, calcium and the basis of left-right asymmetry. BMC Biol 10, 102
(2012).
Viotti, M., Niu, L., Shi, S.-H. & Hadjantonakis, A.-K. Role of the gut endoderm in
relaying left-right patterning in mice. Plos Biol 10, e1001276 (2012).
Saijoh, Y., Viotti, M. & Hadjantonakis, A.-K. Follow your gut: Relaying information
from the site of left-right symmetry breaking in the mouse. Genesis 52, 503–514
(2014).
Saund, R. S. et al. Gut endoderm is involved in the transfer of left-right asymmetry
from the node to the lateral plate mesoderm in the mouse embryo. Development 139,
2426–2435 (2012).
Lopes, S. S. et al. Notch signalling regulates left-right asymmetry through ciliary
length control. Development 137, 3625–3632 (2010).
Yin, C. et al. Hand2
Regulates Extracellular Matrix Remodeling Essential for Gut-Looping Morphogenesis
in Zebrafish. Developmental Cell 18, 973–984 (2010).
Smith, D., Montenegro-Johnson, T. & Lopes, S. Organized chaos in Kupffer's vesicle:
How a heterogeneous structure achieves consistent left-right patterning.
Bioarchitecture 4, 119–125 (2014).
Yuan, S., Zhao, L., Brueckner, M. & Sun, Z. Intraciliary Calcium Oscillations Initiate
Vertebrate Left-Right Asymmetry. Curr. Biol. (2015). doi:10.1016/j.cub.2014.12.051
Wang, G., Manning, M. L. & Amack, J. D. Regional cell shape changes control form
and function of Kupffer's vesicle in the zebrafish embryo. Dev. Biol. 370, 52–62
(2012).
Compagnon, J. et al. The notochord breaks bilateral symmetry by controlling cell
shapes in the zebrafish laterality organ. Developmental Cell 31, 774–783 (2014).
Hojo, M. et al. Right-elevated expression of charon is regulated by fluid flow in
medaka Kupffer's vesicle. Development, Growth & Differentiation 49, 395–405
(2007).
Tanaka, Y., Okada, Y. & Hirokawa, N. FGF-induced vesicular release of Sonic
hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination.
Nature 435, 172–177 (2005).
Essner, J. J.et al. Mesendoderm and left-right brain, heart and gut development are
differentially regulated by pitx2 isoforms. Development 127, 1081–1093 (2000).
Hashimoto, H. et al.The Cerberus/Dan-family protein Charon is a negative regulator
of Nodal signaling during left-right patterning in zebrafish. Development 131, 1741–
1753 (2004).
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