Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos
ABSTRACT Sox7, -17 and -18 constitute the Sox subgroup F (SoxF) of HMG box transcription factor genes, which all are co-expressed in developing vascular endothelial cells in mice. Here we characterized cardiovascular phenotypes of Sox17/Sox18-double and Sox17-single null embryos during early-somite stages. Whole-mount PECAM staining demonstrated the aberrant heart looping, enlarged cardinal vein and mild defects in anterior dorsal aorta formation in Sox17 single-null embryos. The Sox17/Sox18 double-null embryos showed more severe defects in formation of anterior dorsal aorta and head/cervical microvasculature, and in some cases, aberrant differentiation of endocardial cells and defective fusion of the endocardial tube. However, the posterior dorsal aorta and allantoic microvasculature was properly formed in all of the Sox17/Sox18 double-null embryos. The anomalies in both anterior dorsal aorta and head/cervical vasculature corresponded with the weak Sox7 expression sites. This suggests the region-specific redundant activities of three SoxF members along the anteroposterior axis of embryonic vascular network.
- SourceAvailable from: Anna M Method
[Show abstract] [Hide abstract]
- "Moreover, SOX17 is expressed at high levels in the human fetal pancreas and at lower levels in adult islets . It is possible that other SOX proteins in the adult islets compensate for the loss of SOX17 in our Sox17-paLOF mice , , , . For example, SOX4 is the most highly expressed in the islets; it is known to be important for endocrine differentiation, islet organization , and for mediating insulin secretion in response to glucose . "
ABSTRACT: SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1β and FOXA2, which are known to regulate postnatal β cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17-paLOF) had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature β cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17-regulated pathways might be used therapeutically to improve cell function in the context of diabetes.PLoS ONE 08/2014; 9(8):e104675. DOI:10.1371/journal.pone.0104675 · 3.23 Impact Factor
[Show abstract] [Hide abstract]
- "In order to analyze the vascular lacZ expression pattern in more detail and to identify the organ showing lacZ staining, we sectioned the embryos homozygous for CreERT2. We detected lacZ expression in the dorsal aorta and cardinal vein and additionally in the ventral portion of the pancreas (Fig. 2g), which is in line with previous observations (Choi et al., 2012; Engert et al., 2009; Matsui et al., 2006; Sakamoto et al., 2007; Spence et al., 2009). Taken together, early lineage analysis confirmed that the Sox17 CreERT2 line is inducible upon tamoxifen treatment and expresses Cre in the expected cell types. "
ABSTRACT: The HMG-box transcription factor Sox17 is essential for endoderm formation, vascular development and definitive hematopoiesis. To investigate the fate of distinct Sox17 expressing progenitor cells in a spatio-temporal manner, we generated a hormone-inducible CreERT2 knock-in mouse line. By homologous recombination we fused a codon improved, ligand-dependent estrogen receptor Cre recombinase by an intervening viral T2A sequence for co-translational cleavage to the 3' coding region of Sox17. Induction of Cre activity by administration of tamoxifen at defined time points of early mouse development and subsequent genetic lineage tracing confirmed the inducibility and tissue specificity of Cre recombination. Furthermore, Cre activity could be selectively induced in extra-embryonic and embryonic endoderm lineages, the primitive gut tube, and in endothelial cells of the vascular system as well as in the hemogenic endothelium of the dorsal aorta. The Sox17(CreERT2) mouse line therefore represents a new tool for genetic lineage tracing in a tissue-specific manner and in addition enables lineage-restricted functional analysis. © 2013 Wiley Periodicals, Inc.genesis 11/2013; 51(11). DOI:10.1002/dvg.22714 · 2.02 Impact Factor
[Show abstract] [Hide abstract]
- "Of interest , in the absence of Sox18, Sox7 becomes ectopically expressed in the lymphatics (Hosking et al., 2009). Consistent with this, these genes play redundant roles in endothelial cell differentiation in blood and lymphatic vessels in both mice and zebrafish (Cermenati et al., 2008; Sakamoto et al., 2007). In humans, a dominantnegative mutation in human SOX18, which likely interferes with the function of multiple SOX genes, is known to cause Hypotrichosis-Lymphedema- Telangiectasia, a congenital lymphatic disorder (Irrthum et al., 2003). "
ABSTRACT: Mammalian lung development consists of a series of precisely choreographed events that drive the progression from simple lung buds to the elaborately branched organ that fulfills the vital function of gas exchange. Strict transcriptional control is essential for lung development. Among the large number of transcription factors encoded in the mouse genome, only a small portion of them are known to be expressed and function in the developing lung. Thus a systematic investigation of transcription factors expressed in the lung is warranted. To enrich for genes that may be responsible for regional growth and patterning, we performed a screen using RNA in situ hybridization to identify genes that show restricted expression patterns in the embryonic lung. We focused on the pseudoglandular stage during which the lung undergoes branching morphogenesis, a cardinal event of lung development. Using a genome-scale probe set that represents over 90% of the transcription factors encoded in the mouse genome, we identified 62 transcription factor genes with localized expression in the epithelium, mesenchyme, or both. Many of these genes have not been previously implicated in lung development. Our findings provide new starting points for the elucidation of the transcriptional circuitry that controls lung development.Developmental Dynamics 09/2012; 241(9):1432-53. DOI:10.1002/dvdy.23823 · 2.38 Impact Factor