Dullard-mediated Smad1/5/8 inhibition controls mouse cardiac neural crest cells condensation and outflow tract septation

Abstract

The establishment of separated pulmonary and systemic circulation in vertebrates, via cardiac outflow tract (OFT) septation, is a sensitive developmental process accounting for 10% of all congenital anomalies. Neural Crest Cells (NCC) colonising the heart condensate along the primitive endocardial tube and force its scission into two tubes. Here, we show that NCC aggregation progressively decreases along the OFT distal-proximal axis following a BMP signalling gradient. Dullard, a nuclear phosphatase, tunes the BMP gradient amplitude and prevents NCC premature condensation. Dullard maintains transcriptional programs providing NCC with mesenchymal traits. It attenuates the expression of the aggregation factor Sema3c and conversely promotes that of the epithelial-mesenchymal transition driver Twist1. Altogether, Dullard-mediated fine-tuning of BMP signalling ensures the timed and progressive zipper-like closure of the OFT by the NCC and prevents the formation of a heart carrying the congenital abnormalities defining the tetralogy of Fallot.

Ctdnep1 and Eps8L2 regulate dorsal actin cables for nuclear positioning during cell migration

“…How dorsal actin cables are organized to promote TAN lines formation is unknown. Here, we report a role for Ctdnep1/Dullard, a nuclear envelope phosphatase, 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 and the actin regulator Eps8L2 23 , 24 , 25 on nuclear positioning and cell migration. We demonstrate that Ctdnep1 and Eps8L2 directly interact, and this interaction is important for nuclear positioning and cell migration.…”

Heart Development and Congenital Structural Heart Defects

“…Reducing Bmp signaling by depletion of either Bmp4 or the receptor Bmpr1a or by forced expression of the antagonist Smad7 impairs cushion formation and septation of the outflow tract (79,125,129). Conversely, enhancing Bmp signaling by depletion of the inhibitor Ctdnep1 in the neural crest cells leads to premature mesenchyme condensation and septation of the outflow tract, as well as pulmonary artery stenosis (26). One effector of Bmp signaling is the secreted factor Sema3c (26,79).…”

“…Conversely, enhancing Bmp signaling by depletion of the inhibitor Ctdnep1 in the neural crest cells leads to premature mesenchyme condensation and septation of the outflow tract, as well as pulmonary artery stenosis (26). One effector of Bmp signaling is the secreted factor Sema3c (26,79). Cardiac neural crest cells transit through the branchial arches, where they surround a core of other mesodermal cells from the anterior second heart field.…”

The Cardiac Neural Crest Cells in Heart Development and Congenital Heart Defects

“…It is known that cardiac NCCs contribute to the formation of the semilunar valves via OFT septation and communicate with various cell populations. A recent study by Darrigrand and colleagues, in which Dullard (Ctdnep1), a nuclear phosphate known to inhibit Bmps, was deleted in NCCs of mice, resulted in premature and asymmetric OFT septation, pulmonary closure (Figure 1), and embryonic death, due to an increase in Smad1/5/8 activity [85]. Additionally, the removal of Ctdnep1 in mice significantly decreased the expression of Twist1, Snai1, Rac1, Mmp14, and Chd2, known mesenchymal markers, resulting in premature NCC compaction [85].…”

“…A recent study by Darrigrand and colleagues, in which Dullard (Ctdnep1), a nuclear phosphate known to inhibit Bmps, was deleted in NCCs of mice, resulted in premature and asymmetric OFT septation, pulmonary closure (Figure 1), and embryonic death, due to an increase in Smad1/5/8 activity [85]. Additionally, the removal of Ctdnep1 in mice significantly decreased the expression of Twist1, Snai1, Rac1, Mmp14, and Chd2, known mesenchymal markers, resulting in premature NCC compaction [85]. Stottmann and colleagues found that the ablation of the Bmp receptor 1A (Bmpr1a) in NCCs, by Wnt1-Cre in mice, resulted in shortened OFTs with septation defects (PTA), embryonic lethality due to acute heart failure, and occasional hypoplastic aortic arch arteries, indicating that Bmp signaling is required for proper OFT development (Figure 1) [86].…”