SOX9 controls epithelial branching by activating RET effector genes during kidney development

Reginensi, Antoine; Clarkson, Michael W.; Neirijnck, Yasmine; Lu, Benson; Ohyama, Takahiro; Groves, Andrew K.; Sock, Elisabeth; Wegner, Michael; Costantini, Frank; Chaboissier, Marie-Christine; Schedl, Andreas

doi:10.1093/hmg/ddq558

Cited by 118 publications

(93 citation statements)

References 42 publications

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“…Sox9 belongs to SOX group E (SoxE), along with Sox8 and Sox10 (Foster et al, 1994). Sox9 has important functions in the development of several organs, including the liver, pancreas, lung and kidney (Furuyama et al, 2011;Reginensi et al, 2011;Seymour et al, 2012;Chang et al, 2013;Rockich et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands

et al. 2014

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Murine lacrimal, harderian and meibomian glands develop from the prospective conjunctival and eyelid epithelia and produce secretions that lubricate and protect the ocular surface. Sox9 expression localizes to the presumptive conjunctival epithelium as early as E11.5 and is detected in the lacrimal and harderian glands as they form. Conditional deletion showed that Sox9 is required for the development of the lacrimal and harderian glands and contributes to the formation of the meibomian glands. Sox9 regulates the expression of Sox10 to promote the formation of secretory acinar lobes in the lacrimal gland. Sox9 and FGF signaling were required for the expression of cartilageassociated extracellular matrix components during early stage lacrimal gland development. Fgfr2 deletion in the ocular surface epithelium reduced Sox9 and eliminated Sox10 expression. Sox9 deletion from the ectoderm did not affect Fgf10 expression in the adjacent mesenchyme or Fgfr2 expression in the epithelium, but appeared to reduce FGF signaling. Sox9 heterozygotes showed a haploinsufficient phenotype, in which the exorbital branch of the lacrimal gland was absent in most cases. However, enhancement of epithelial FGF signaling by expression of a constitutively active FGF receptor only partially rescued the lacrimal gland defects in Sox9 heterozygotes, suggesting a crucial role of Sox9, downstream of FGF signaling, in regulating lacrimal gland branching and differentiation.

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Section: Discussionmentioning

confidence: 99%

FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands

et al. 2014

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“…One intriguing candidate is Sox9, which is highly expressed in distal epithelial cells undergoing active branching (21) (Fig. 3) and required for the development of two other branched organs, the kidney and the pancreas (34,35). To test the role of Sox9 in mouse lung development, we deleted it specifically in the epithelium with a Shh Cre allele (16,17).…”

Section: Negative Correlations Between Branching Morphogenesis and Almentioning

confidence: 99%

Lung epithelial branching program antagonizes alveolar differentiation

Chang¹,

Alanis²,

Miller

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

171

231

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Mammalian organs, including the lung and kidney, often adopt a branched structure to achieve high efficiency and capacity of their physiological functions. Formation of a functional lung requires two developmental processes: branching morphogenesis, which builds a tree-like tubular network, and alveolar differentiation, which generates specialized epithelial cells for gas exchange. Much progress has been made to understand each of the two processes individually; however, it is not clear whether the two processes are coordinated and how they are deployed at the correct time and location. Here we show that an epithelial branching morphogenesis program antagonizes alveolar differentiation in the mouse lung. We find a negative correlation between branching morphogenesis and alveolar differentiation temporally, spatially, and evolutionarily. Gain-of-function experiments show that hyperactive small GTPase Kras expands the branching program and also suppresses molecular and cellular differentiation of alveolar cells. Loss-of-function experiments show that SRYbox containing gene 9 (Sox9) functions downstream of Fibroblast growth factor (Fgf)/Kras to promote branching and also suppresses premature initiation of alveolar differentiation. We thus propose that lung epithelial progenitors continuously balance between branching morphogenesis and alveolar differentiation, and such a balance is mediated by dual-function regulators, including Kras and Sox9. The resulting temporal delay of differentiation by the branching program may provide new insights to lung immaturity in preterm neonates and the increase in organ complexity during evolution.

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“…It has been reported that Pou3f3 (Nakai et al, 2003), Dll1 (Kobayashi et al, 2008b), Sox9 (Reginensi et al, 2011), Dkk1, Papss2, Greb1, Pcsk9, Lhx1 and Bmp2 (Georgas et al, 2009) are expressed specifically in the distal RV, whereas Cdh6 (Cho et al, 1998), Wt1 and Tmem100 (Georgas et al, 2009) are expressed in the proximal RV. In addition, Ccnd1, Jag1, Ccdc86 and Wnt4 were reported to be expressed throughout the RV, but with higher expression in distal than proximal regions (Georgas et al, 2009).…”

Section: Single Cell Analysis Of the Renal Vesiclementioning

confidence: 99%

Single cell dissection of early kidney development: multilineage priming

et al. 2014

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We used a single cell RNA-seq strategy to create an atlas of gene expression patterns in the developing kidney. At several stages of kidney development, histologically uniform populations of cells give rise to multiple distinct lineages. We performed single cell RNA-seq analysis of total mouse kidneys at E11.5 and E12.5, as well as the renal vesicles at P4. We define an early stage of progenitor cell induction driven primarily by gene repression. Surprising stochastic expression of marker genes associated with differentiated cell types was observed in E11.5 progenitors. We provide a global view of the polarized gene expression already present in the renal vesicle, the first epithelial precursor of the nephron. We show that Hox gene readthrough transcripts can be spliced to produce intergenic homeobox swaps. We also identify a surprising number of genes with partially degraded noncoding RNA. Perhaps most interesting, at early developmental times single cells often expressed genes related to several developmental pathways. This provides powerful evidence that initial organogenesis involves a process of multilineage priming. This is followed by a combination of gene repression, which turns off the genes associated with most possible lineages, and the activation of increasing numbers of genes driving the chosen developmental direction.

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SOX9 controls epithelial branching by activating RET effector genes during kidney development

Cited by 118 publications

References 42 publications

FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands

FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands

Lung epithelial branching program antagonizes alveolar differentiation

Single cell dissection of early kidney development: multilineage priming

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