We report that Sonic Hedgehog (Shh) regulates both formation and patterning of tracheal cartilage by controlling the expression pattern and level of the chondrogenic gene, Sox9. In Shh 2/2 tracheo-esophageal tubes, Sox9 expression is transient and not restricted ventrally to the site of chondrogenesis, and is absent at the time of chondrogenesis, resulting in the failure of tracheal cartilage formation. Inhibition of Hedgehog signalling with cyclopamine in tracheal cultures prevents tracheal cartilage formation, while treatment of Shh 2/2 tracheal explant with exogenous Shh peptide rescues cartilage formation. Both exogenous Bmp4 and Noggin rescue cartilage phenotype in Shh 2/2 tracheal culture, while promoting excessive cartilage development in wild-type trachea through induction of Sox9 expression. The ventral and segmented expression of Sox9 in tracheal primordia under Shh modulated by Bmp4 and Noggin thus determine where and when tracheal cartilage develops. These results indicate that Shh signalling is a critical determinant in tracheal cartilage development. Developmental Dynamics 239:514-526,
The bladder, the largest smooth-muscle organ in the human body, is responsible for urine storage and micturition. P63, a homolog of the p53 tumor-suppressor gene, is essential for the development of all stratified epithelia, including the bladder urothelium. The N-terminal truncated isoform of p63, ⌬Np63, is known to have anti-apoptotic characteristics. We have established that ⌬Np63 is not only the predominant isoform expressed throughout the bladder, but is also preferentially expressed in the ventral bladder urothelium during early development. We observed a host of ventral defects in p63 -/-embryos, including the absence of the abdominal and ventral bladder walls. This number of ventral defects is identical to bladder exstrophy, a congenital anomaly exhibited in human neonates. In the absence of p63, the ventral urothelium was neither committed nor differentiated, whereas the dorsal urothelium was both committed and differentiated. Furthermore, in p63 -/-bladders, apoptosis in the ventral urothelium was significantly increased. This was accompanied by the upregulation of mitochondrial apoptotic mediators Bax and Apaf1, and concurrent upregulation of p53. Overexpression of ⌬Np63␥ and ⌬Np63 in p63 -/-bladder primary cell cultures resulted in a rescue, evidenced by significantly reduced expressions of Bax and Apaf1. We conclude that ⌬Np63 plays a crucial anti-apoptotic role in normal bladder development.
We report the case of a 6-year-old female with xeroderma pigmentosum (XP) who developed a nonoperable scalp tumor, treated with anti-programmed cell death protein 1 (anti-PD-1) therapy (nivolumab). She presented with a sarcomatoid carcinoma of the scalp with bone lysis as well as vascular and meningeal contact. Nivolumab was initiated because it has emerged as a promising immunotherapy. We observed a dramatic tumor response with excellent tolerance. However, while on nivolumab therapy she developed two large skin melanomas and several squamous cell carcinomas, which have been resected. These results demonstrate that cancer immunotherapy in patients with XP can be impressive but complex and warrants further investigation.
Patterning and differentiation along the dorsal-ventral (D-V) axis lead to cloacal partitioning into ventral urinary and dorsal alimentary tracts in most mammals, but not birds and fish. We previously reported that the major activator of Sonic hedgehog (Shh) signaling transcription factor Gli2 plays an essential role in cloacal partitioning along the D-V axis in a mouse model. Here, we report that chick cloacal patterning and differentiation is along the anterior-posterior axis. During chick cloacal formation, Shh is expressed strongly in hindgut endoderm; Gli2 is very weakly detected in the surrounding hindgut mesoderm. In the mesoderm of the cloacal region, the over-expression of the constitutively active form of mouse Gli2 has been shown to: not induce cloacal partitioning along the D-V axis; induce expression of Ptch1, Gli2, bmp4, wnt5a, and hoxd-13, which have been previously shown to play a role in hindgut patterning; increase cell proliferation; and reduce apoptosis. Interestingly, p63 expression in the cloacal endoderm is also up-regulated, suggesting an interaction between the Shh and p63 pathways. In conclusion, Gli2 alone is insufficient to induce partitioning along the D-V axis in the chick embryo. However, Gli2 regulates both epithelial and mesenchymal cell proliferation and apoptosis during cloacal development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.