Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development

Reidy, Kimberly; Villegas, G.; Teichman, Jason; Verón, Delma; Shen, Wa; Jiménez, Juan Jiménez; Thomas, David B.; Tufró, Alda

doi:10.1242/dev.037267

Cited by 88 publications

(105 citation statements)

References 63 publications

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“…Ostensibly because of genetic heterogeneity due to different maintenance this was not observed in another colony of Sema3a null CD-1 mice (Vieira et al, 2007). However, in further support for a role of SEMA3A in vascular remodeling, it has been recently reported that Sema3a deletion in an inbred strain results in defective renal vascular patterning (Reidy et al, 2009). Notably, in the same Sema3a null mice both Sema3b and Sema3e mRNA were found to be up-regulated (Reidy et al, 2009), thus providing a molecular mechanism by which compensation can occur in Sema3a null mice (Vieira et al, 2007).…”

Section: Semaphorins and Vascular Developmentmentioning

confidence: 95%

Nervous vascular parallels: axon guidance and beyond

Arese¹,

Serini

Bussolino

2011

Int. J. Dev. Biol.

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The vascular and nervous systems are organized with well defined and accurate networks, which represent the anatomical structure enabling their functions. In recent years, it has been clearly demonstrated that these two systems share in common several mechanisms and specificities. For instance, the networking properties of the nervous and vascular systems are governed by common cues that in the brain regulate axon connections and in the vasculature remodel the primitive plexus towards the vascular tree. Here, we summarize the role of semaphorins as a paradigmatic example of the role of axon guidance molecules in physiological and pathological angiogenesis. Finally, we discuss the presence in blood vessels of neurexin and neuroligin, two proteins that finely modulate synaptic activity in the brain. This observation is suggestive of an intriguing new class of molecular and functional parallels between neurons and vascular cells.

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Section: Semaphorins and Vascular Developmentmentioning

confidence: 95%

Nervous vascular parallels: axon guidance and beyond

Arese¹,

Serini

Bussolino

2011

Int. J. Dev. Biol.

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“…Various growth factor/receptor signaling pathways, including FGFs, bone morphogenic proteins, VEGF, semaphorins, hepatocyte growth factor, EGF, among others, share signaling components with the c-Ret pathway and are required for optimal metanephric growth and patterning (15)(16)(17)(18)(19)(20)(21)(22). Following induction of the MM, activation of the Wnt/␤-catenin signaling pathway plays a key role in nephrogenesis.…”

mentioning

confidence: 99%

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation

Chen

Bellew

Xiao

et al. 2011

Journal of Biological Chemistry

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Histone deacetylases (HDACs) regulate fundamental biological processes such as cellular proliferation, differentiation, and survival via genomic and nongenomic effects. This study examined the importance of HDAC activity in the regulation of gene expression and differentiation of the developing mouse kidney. Class I HDAC1-3 and class II HDAC4, -7, and -9 genes are developmentally regulated. Moreover, HDAC1-3 are highly expressed in nephron precursors. Short term treatment of cultured mouse embryonic kidneys with HDAC inhibitors (HDACi) induced global histone H3 and H4 hyperacetylation and H3K4 hypermethylation. However, genome-wide profiling revealed that the HDAC-regulated transcriptome is restricted and encompasses regulators of the cell cycle, Wnt/␤-catenin, TGF-␤/Smad, and PI3K-AKT pathways. Further analysis demonstrated that base-line expression of key developmental renal regulators, including Osr1, Eya1, Pax2/8, WT1, Gdnf, Wnt9b, Sfrp1/2, and Emx2, is dependent on intact HDAC activity. Treatment of cultured embryonic kidney cells with HDACi recapitulated these gene expression changes, and chromatin immunoprecipitation assays revealed that HDACi is associated with histone hyperacetylation of Pax2/Pax8, Gdnf, Sfrp1, and p21. Gene knockdown studies demonstrated that HDAC1 and HDAC2 play a redundant role in regulation of Pax2/8 and Sfrp1 but not Gdnf. Long term treatment of embryonic kidneys with HDACi impairs the ureteric bud branching morphogenesis program and provokes growth arrest and apoptosis. We conclude that HDAC activity is critical for normal embryonic kidney homeostasis, and we implicate class I HDACs in the regulation of early nephron gene expression, differentiation, and survival.Kidney development depends on reciprocal inductive interactions between the metanephric mesenchyme (MM), 4 a specified region in the caudal intermediate mesoderm, and the ureteric bud (UB), an epithelial outgrowth from the Wolffian (nephric) duct (1-3). Recent years have witnessed significant progress in our understanding of the gene regulatory networks of early kidney development (3-6). For example, the Osr1/ Eya1/Pax2/Six/Sall/WT1/Hoxd11 gene regulatory network specifies the MM and is absolutely required for expression of glia-derived neurotrophic factor (Gdnf) (7,8). Gdnf, in turn, is essential for UB outgrowth and subsequent branching (9 -11).Gdnf acts via activation of a c-Ret/PI3K/ERK-dependent gene network (Wnt11, Spry1, Etv4, Etv5, Cxcr4, Myb, Met, and Mmp14) in UB tip cells to control the branching morphogenesis program (12-14). Various growth factor/receptor signaling pathways, including FGFs, bone morphogenic proteins, VEGF, semaphorins, hepatocyte growth factor, EGF, among others, share signaling components with the c-Ret pathway and are required for optimal metanephric growth and patterning (15)(16)(17)(18)(19)(20)(21)(22). Following induction of the MM, activation of the Wnt/␤-catenin signaling pathway plays a key role in nephrogenesis. Release of Wnt9b from the UB branches triggers a ␤-catenindependent mo...

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“…64 Furthermore, it has been suggested that there is functional competition between sema3a and VEGF. 65 Therefore, it is possible that Tak1 deletion-induced overexpression of VEGF suppresses the function of sema3a that leads to multiple endothelial cell defects.…”

Section: Discussionmentioning

confidence: 99%

TGF-β–Activated Kinase 1 Is Crucial in Podocyte Differentiation and Glomerular Capillary Formation

Kim

Lee

Wang

et al. 2014

Journal of the American Society of Nephrology

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TGF-b-activated kinase 1 (TAK1) is a key intermediate in signal transduction induced by TGF-b or inflammatory cytokines, such as TNF-a and IL-1, which are potent inducers of podocyte injury responses that lead to proteinuria and glomerulosclerosis. Nevertheless, little is known about the physiologic and pathologic roles of TAK1 in podocytes. To examine the in vivo role of TAK1, we generated podocyte-specific Tak1 knockout mice (Nphs2-Cre mice, Tak1 Δ/Δ mice exhibited impaired formation of podocyte foot processes that caused disruption of the podocyte architecture with prominent foot process effacement. Intriguingly, Tak1 Δ/Δ mice displayed increased expression of vascular endothelial growth factor within the glomerulus and abnormally enlarged glomerular capillaries. Furthermore, 4-and 7-week-old Tak1 Δ/Δ mice with proteinuria had increased collagen deposition in the mesangium and the adjacent tubulointerstitial area. Thus, loss of Tak1 in podocytes is associated with the development of proteinuria and glomerulosclerosis. Taken together, our data show that TAK1 regulates the expression of Wilms' tumor suppressor 1, nephrin, and vascular endothelial growth factor and that TAK1 signaling has a crucial role in podocyte differentiation and attainment of normal glomerular microvasculature during kidney development and glomerular filtration barrier homeostasis.

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Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development

Cited by 88 publications

References 63 publications

Nervous vascular parallels: axon guidance and beyond

Nervous vascular parallels: axon guidance and beyond

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation

TGF-β–Activated Kinase 1 Is Crucial in Podocyte Differentiation and Glomerular Capillary Formation

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