Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells.

The pancreas is an endodermally derived organ that initially appears as a dorsal and ventral protrusion of the primitive gut epithelium. The pancreatic progenitor cells present in these early pancreatic anlagen proliferate and eventually give rise to all pancreatic cell types. The fibroblast growth factor receptor (FGFR) 2b high-affinity ligand FGF10 has been linked to pancreatic epithelial cell proliferation, and we have shown previously that Notch signalling controls pancreatic cell differentiation by means of lateral inhibition. In the developing pancreas, activated intracellular Notch appears to be required for maintaining cells in the progenitor state, in part by blocking the expression of the pro-endocrine gene neurogenin 3 (ngn3), and hence endocrine cell differentiation. Here, we show that persistent expression of Fgf10 in the embryonic pancreas of transgenic mice also inhibits pancreatic cell differentiation, while stimulating pancreatic epithelial cell proliferation. We provide evidence that one of the effects of the persistent expression of Fgf10 in the developing pancreas is maintained Notch activation, which results in impaired expression of ngn3 within the pancreatic epithelium. Together, our data suggest a role for FGF10/FGFR2b signalling in regulation of pancreatic cell proliferation and differentiation and that FGF10/FGFR2b signalling affects the Notch-mediated lateral inhibition pathway.     

常染色质组蛋白甲基化转移酶与哺乳动物生殖

常染色质组蛋白甲基化转移酶(euchromatin histone lysine methyltransferases,EHMTs)能够使基因组常染色质区域的组蛋白3第9位赖氨酸二甲基化(histone 39th lysine demethylate,H3K9-di).在哺乳动物中有两种EHMT基因编码蛋白,分别为EHMT1编码GLP和EHMT2编码G9a.EHMTs在不同组织和不同细胞分化的过程中扮演不同的角色并且参与到记忆、药物成瘾、免疫反应等成人特异性反应过程的形成.EHMTs及其蛋白在哺乳动物生殖过程中的配子发生、胚胎发育及子宫疾病等方面发挥重要的作用.     

Dll3 is expressed in developing hair cells in the mammalian cochlea.

Notch mediates the process of lateral inhibition that controls the production of hair cells in the inner ear. Hair cells are known to express Notch ligands Dll1 and Jag2, which signal through Notch1 in adjacent supporting cells. However, recent genetic and pharmacological studies indicate that the level of Notch-mediated lateral inhibition is greater than can be accounted for by Dll1 and Jag2. Here, we report that another Notch ligand, Dll3, is expressed in developing hair cells, in a pattern that overlaps that of Dll1 and Jag2. We analyzed the cochleae of Dll3(pu) mutant mice, but did not detect any abnormalities. However, earlier studies have demonstrated that there is functional redundancy among Notch ligands in cochlear development and loss of one ligand can be at least partially compensated for by another. Thus Dll3 may play a role in lateral inhibition similar to that of Dll1 and Jag2.     

Mechanisms of ligand‐mediated inhibition in Notch signaling activity in Drosophila

The transmembrane proteins Delta and Serrate act as ligands for the signaling receptor Notch. In addition to this activating role, Delta and Serrate can also inhibit Notch signaling activity. This inhibitory effect is concentration‐dependent and appears to be evolutionarily conserved. In characterizing the underlying cellular mechanisms of the ligand inhibitory effect, we can confirm that ligand‐mediated inhibition of Notch signaling can occur as a cell autonomous process (cis‐inhibition) and that ligand‐mediated inhibition prevents a step in Notch signaling activation early enough to suppress Notch ectodomain shedding. Developmental Dynamics 239:798–805, 2010. © 2010 Wiley‐Liss, Inc.     

Notch in the kidney: development and disease

Notch signalling is a highly conserved cell-cell communication mechanism that regulates development, tissue homeostasis, and repair. Within the kidney, Notch has an important function in orchestrating kidney development. Recent studies indicate that Notch plays a key role in establishing proximal epithelial fate during nephron segmentation as well as the differentiation of principal cells in the renal collecting system. Notch signalling is markedly reduced in the adult kidney; however, increased Notch signalling has been noted in both acute and chronic kidney injury. Increased glomerular epithelial Notch signalling has been associated with albuminuria and glomerulosclerosis, while tubular epithelial Notch activation caused fibrosis development most likely inducing an improper epithelial repair pathway. Recent studies thereby indicate that Notch is a key regulator of kidney development, repair, and injury.     

Notch信号通路在骨重建中的作用

Notch信号通路在胚胎发育、神经系统、血管系统、内分泌系统及肿瘤等领域具有广泛的影响。近年来的研究表明,Notch对于骨组织代谢尤其是骨重建有着重要的调控作用,而骨重建的调节紊乱和骨质疏松、骨关节炎等疾病的进展密切相关。Notch信号通路可以通过调控骨组织不同细胞的功能从而影响骨重建过程,但其在不同细胞中具体的参与方式仍然未知。综述近年来Notch信号通路在骨重建中的作用研究进展。     

Dichotomy of Notch signalling in regulating tumour immune surveillance

Notch signalling is an evolutionarily conserved multifaceted pathway that controls diverse cellular processes. Its role in regulating development and tissue homeostasis is well established. Aberrant activation of the Notch pathway has been implicated in the initiation and progression of many types of cancers. However, although in some cancers Notch signalling acts as a tumour‐promoter, in others it is reported to suppress tumour growth and progression. Accumulating evidence suggests the involvement of both the innate and adaptive immune system in the development of various tumours. Currently, extensive studies on investigating the effects of Notch signalling in tumour immune surveillance are being carried out. Interestingly, recent literature shows how the changing expression of Notch genes in different T cell subsets like CD4 and CD8 helps in controlling anti‐tumour immune responses. In this review, we discuss in depth the roles of Notch signalling molecules and different immune cells in the context of the tumour microenvironment. We also outline how current knowledge can be exploited to develop novel therapies in order to control the propagation of cancer stem cells.     

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.