Ectodermal Smad4 and p38 MAPK Are Functionally Redundant in Mediating TGF-β/BMP Signaling during Tooth and Palate Development

Xu, Xun; Han, Jun; Ito, Yoshihiro; Bringas, Pablo; Deng, Chu‐Xia; Chai, Yang

doi:10.1016/j.devcel.2008.06.004

Cited by 130 publications

(148 citation statements)

References 31 publications

(45 reference statements)

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“…The roles of Smad4-independent Tgf signaling during development have recently been reported. During development of the palate, a Smad4-independent Tgf pathway, which is mediated by a p38 kinase pathway, is involved in palate fusion (Xu et al, 2008). Smad4-independent Tgf signaling also plays a role in cardiac (Song et al, 2007) and sensory nervous system development (Hodge et al, 2007) through unknown pathways.…”

Section: Sns Development Is Regulated By a Smad4-independent Bmp Pathwaymentioning

confidence: 99%

BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways

et al. 2009

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Induction of the sympathetic nervous system (SNS) from its neural crest (NC) precursors is dependent on BMP signaling from the dorsal aorta. To determine the roles of BMP signaling and the pathways involved in SNS development, we conditionally knocked out components of the BMP pathways. To determine if BMP signaling is a cell-autonomous requirement of SNS development, the Alk3 (BMP receptor IA) was deleted in the NC lineage. The loss of Alk3 does not prevent NC cell migration, but the cells die immediately after reaching the dorsal aorta. The paired homeodomain factor Phox2b, known to be essential for survival of SNS precursors, is downregulated, suggesting that Phox2b is a target of BMP signaling. To determine if Alk3 signals through the canonical BMP pathway, Smad4 was deleted in the NC lineage. Loss of Smad4 does not affect neurogenesis and ganglia formation; however, proliferation and noradrenergic differentiation are reduced. Analysis of transcription factors regulating SNS development shows that the basic helix-loop-helix factor Ascl1 is downregulated by loss of Smad4 and that Ascl1 regulates SNS proliferation but not noradrenergic differentiation. To determine if the BMP-activated Tak1 (Map3k7) pathway plays a role in SNS development, Tak1 was deleted in the NC lineage. We show that Tak1 is not involved in SNS development. Taken together, our results suggest multiple roles for BMP signaling during SNS development. The Smad4-independent pathway acts through the activation of Phox2b to regulate survival of SNS precursors, whereas the Smad4-dependent pathway controls noradrenergic differentiation and regulates proliferation by maintaining Ascl1 expression.

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Section: Sns Development Is Regulated By a Smad4-independent Bmp Pathwaymentioning

confidence: 99%

BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways

et al. 2009

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“…Smad4 was detected by a mouse monoclonal anti-Smad4 antibody (Sc-7966; Santa Cruz) raised against amino acids 1-552 representing the full-length Smad4 human protein as described earlier. 36 Laminin a1 antibody was provided by Jeffrey H. Miner (Washington University, St. Louis, MO). Appropriate AlexaFlour488-or -555-conjugated secondary antibodies (1:1000; Molecular Probe) were used to detect the corresponding primary antibodies.…”

Section: Histologic Analysis and Immunohistochemistrymentioning

confidence: 99%

Absence of Canonical Smad Signaling in Ureteral and Bladder Mesenchyme Causes Ureteropelvic Junction Obstruction

Tripathi

Wang²,

Casey³

et al. 2012

Journal of the American Society of Nephrology

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Obstruction of the ureteropelvic junction (UPJ) is a common congenital anomaly frequently associated with ureteral defects. To study the molecular mechanisms that modulate ureteral development, we inactivated Smad4, the common Smad critical for transcriptional responses to TGF-b and Bmp signaling, in the ureteral and bladder mesenchyme during embryogenesis. Loss of canonical Smad signaling in these tissues caused bilateral UPJ obstruction and severe hydronephrosis beginning at embryonic day 17.5. Despite a reduction in quantity of ureteral smooth muscle, differentiation proceeded without Smad4, producing a less severe phenotype than Bmp4 mutants; this finding suggests that at least some Bmp4 functions in ureteral smooth muscle may be Smad-independent. The absence of canonical Smad signaling in the ureteral mesenchyme, but not in the urothelium itself, led to urothelial disorganization, highlighting the importance of mesenchymal support for epithelial development. Transcript profiling revealed altered expression in known Bmp targets, smooth muscle-specific genes, and extracellular matrix-related genes in mutant ureters before the onset of hydronephrosis. Expression of the Bmp target Id2 was significantly lower in Smad4 mutants, consistent with the observation that Id2 mutants develop UPJ obstruction. In summary, Smad4 deficiency reduces the number and contractility of ureteral smooth muscle cells, leading to abnormal pyeloureteral peristalsis and functional obstruction. The subsequent bending and luminal constriction of the ureter at the UPJ marks the transition from a functional obstruction to a more intractable physical obstruction, suggesting that early intervention for this disease may prevent more irreversible damage to the urinary tract.

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“…Although p38 MAPK has been shown to regulate the process of palatal fusion, the role of p38MAPK has not been examined in the palatal MEE adhesion stage (Xu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Palatal adhesion is dependent on Src family kinases and p38MAPK

Kitase¹,

Shuler²

2014

Int. J. Dev. Biol.

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During secondary palate development, palatal shelves adhere to each other in the midline to form a midline epithelial seam leading to palatal closure. Cell-cell and cell-extracellular matrix adhesions, which are mediated by cell adhesion receptors, E-cadherin and integrins, are implicated in the process of adhesion of the palatal shelves. Src family kinases (SFK) function downstream of both receptors. In this study, we focused on the role of SFK in the process of palatal adhesion. During palatal adhesion, the expression of SFK mRNA, as well as localization and quantitation of the protein in the activated form, were examined by real-time qPCR and immunofluorescence. Palatal organ cultures were performed to identify the effect of pharmacological inhibition of SFK on palatal adhesion. Activated SFKs were found to be co-localized with adhesion receptors, E-cadherin and integrins in the palatal medial edge epithelium. Src, Fyn and Yes subfamily members were expressed in the palatal tissue. The expression of SFK mRNA and the quantity of the activated form of the protein were upregulated during palatal adhesion. An SFK inhibitor, PP2, blocked palatal adhesion, but another SFK inhibitor, SU6656 was not inhibitory. However, the combination of SU6656 and either of the p38MAPK inhibitors, SB203580 or BIRB0796, showed similar inhibitory effects on palatal adhesion compared to PP2 alone. The p38MAPK inhibitors alone did not alter palatal adhesion. Real-time qPCR revealed that p38MAPK a and d were elevated during palatal adhesion. This study indicates that palatal cell adhesion is dependent on signaling from integrin receptors and E-cadherin through SFK and p38MAPK.

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Ectodermal Smad4 and p38 MAPK Are Functionally Redundant in Mediating TGF-β/BMP Signaling during Tooth and Palate Development

Cited by 130 publications

References 31 publications

BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways

BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways

Absence of Canonical Smad Signaling in Ureteral and Bladder Mesenchyme Causes Ureteropelvic Junction Obstruction

Palatal adhesion is dependent on Src family kinases and p38MAPK

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