Notch3 is a genetic modifier of NODAL signalling for patterning asymmetry during mouse heart looping
Posted on: 6 June 2024
Preprint posted on 28 March 2024
How to decide at which side to loop the heart tube? Notch3 holds a clue...
Selected by Bhaval Parmar
Categories: biochemistry, cell biology, developmental biology, molecular biology
Background
Left-right patterning of the embryo is crucial for the proper development of visceral organs. Disruptions in this process can lead to heterotaxy syndrome, a severe condition often characterized by complex congenital heart defects. The mechanisms underlying symmetry-breaking are well understood in mice. The chirality of tubulin drives the rotational movement of motile cilia in the node, creating a leftward fluid flow detected by crown cells. This results in the asymmetric expression of the left determinant NODAL in the lateral plate mesoderm. Genetic mutations affecting the node’s formation, ciliogenesis, or NODAL signaling are linked to heterotaxy in both mice and humans.
NODAL signaling influences organ precursors, guiding morphogenesis in organs like the intestine and heart. Without NODAL, certain features remain symmetrical, but others, such as heart looping and stomach positioning, exhibit abnormal asymmetry. This suggests that factors beyond NODAL signaling contribute to asymmetry.
Research shows that NODAL is not necessary for the initiation of heart looping. However, in NODAL-deficient embryos, heart asymmetries are reduced, and the helical shape of the looped heart tube is abnormal. The arterial and venous poles exhibit random orientations, resulting in four classes of abnormal heart loops. NODAL signaling is transient, occurring before heart tube formation (E8.5), in precursor cells of the heart tube poles. As cardiac precursor cells incorporate into the heart tube, they drive its elongation. While molecular profiling and fate mapping have been used to study the patterning of cardiac precursors, only the NODAL signaling pathway has been looked at to explain the left-right patterning. This study links NODAL signaling with Notch3 expression which occurs in lateral plate mesoderm. The preprint authors demonstrate that Notch3 is a potent regulator of left-right symmetry along with NODAL.
Key contributions
The authors of this preprint identified a new contributor to heart tube looping: Notch3. NODAL, a known factor governing the left-right symmetry of the developing embryo, partially influences the looping of the developing heart tube. However, NODAL alone cannot determine the heart tube’s looping pattern; Notch3 also participates in this process. RNA sequencing and conditional mutation data indicate that Notch3 and NODAL together determine the symmetry of the developing heart tube. The following points are the key findings presented in this preprint:
1. A single Notch3 mutation in the developing embryo did not lead to any defects in the heart tube’s looping pattern.
2. Notch3 double mutants exhibited congenital heart defects, such as abnormal ventricle formation, possibly due to Notch3’s significant role in muscle cell differentiation alongside NODAL.
3. Notch3 is expressed in cardiac precursor cells but not in cardiomyocytes, indicating its role during the early patterning of the heart tube.
4. NODAL and Notch3 function together through TDGF1 and follow Notch signaling to determine the symmetry and looping of the heart tube.
Why I picked this preprint
Collectively, these findings shed light on the complexity of left-right symmetry in vertebrates. The symmetry of the developing organism is not defined by a single regulator; rather, it often involves shared roles, such as those of Notch3 and NODAL in heart looping. Current research in symmetry specification helps us understand defects related to faulty organ patterning.
Questions/Future directions
1. In this study, exploring how Notch3 interacts with various transcription factors responsible for heart looping may provide a broad understanding of Notch3 functions.
2. Is there an upstream regulator of Notch3 that controls the Notch3 transient expression pattern in the developing heart region?
3. What are the intermediate molecules that regulate Notch3 signaling and lead to changes in the looping pattern of the heart tube?
doi: https://doi.org/10.1242/prelights.37602
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