A splice variant of the Wilms' tumour suppressorWt1is required for normal development of the olfactory system

Abstract

Neuronal lineage formation in the developing olfactory epithelium has been extensively studied at the cellular level, but little is known about the genes that control proliferation and differentiation of neuronal progenitor cells. Here, we report that the Wilms' tumour zinc-finger protein, Wt1, is required for normal formation of the olfactory epithelium. Wt1 was detected by immunohistochemistry in the developing olfactory epithelium of wild-type embryos between gestational days E9.5 and E18.5. Embryos with complete lack of Wt1 and embryos with selective ablation of the alternatively spliced Wt1(+KTS) isoform both had thinner olfactory epithelia and fewer neuronal progenitor cells than do normal animals. Mash1 and neurogenin 1, two basic helix-loop-helix transcription factors with critical functions during olfactory neuron development, were reduced in the Wt1(+KTS)-/- mutants compared with the wild-type mice. Stable expression of the Wt1(+KTS) isoform, but not of the Wt1(-KTS) variant, upregulated Mash1 mRNA and protein in vitro. The olfactory epithelia of mouse embryos, which lacked the Wt1(-KTS)protein, appeared normal. However, formation of the neural retina was severely impaired in the Wt1(-KTS)-/- mutants. These findings demonstrate that the Wt1(+KTS) protein, which has been proposed to play a role in mRNA processing, acts upstream of Mash1 to promote the development of the olfactory epithelium. Furthermore, neuron formation depends on distinct functions of alternatively spliced Wt1 products in the embryonic retina and the olfactory epithelium.

The epicardium as modulator of the cardiac autonomic response during early development

“…Wt1, a transcription factor expressed in the embryonic PEO and epicardium, is necessary for normal epicardial and cardiac development [27]. The current manuscript shows WT1/TUBB3 coexpression in the central nervous system, which is in agreement with previous reports demonstrating an important role for Wt1 in neural functioning [28][29][30][31][32].…”

The Wilms’ tumor 1 (WT1) gene (+KTS isoform) functions with a CTE to enhance translation from an unspliced RNA with a retained intron

“…However, although a transcriptional role for a chimeric Ewing's Sarcoma gene (EWS)-WT1(+KTS) protein has been described (Reynolds et al 2003), no clear function has been attributed to the native WT1(+KTS) protein, in spite of the fact that proper +KTS/−KTS ratios are crucial in the development of several organs (Hammes et al 2001;Davies et al 2004;Wagner et al 2005). In this study, we have shown for the first time that WT1(+KTS) functions at the post-transcriptional level to regulate RNA expression and, specifically, that the +KTS protein can function in conjunction with a cis-acting CTE to promote translation of an unspliced RNA with a retained intron.…”

“…Specifically, retention of the single small intron in the Id3 gene after vascular injury results in expression of an alternative protein isoform, which appears to function as a modulator of the protein expressed from the spliced RNA (Matsumura et al 2001;Forrest et al 2004). This may be particularly relevant, since a recent study demonstrated that deletion of the WT1(+KTS) isoform affected the expression of MASH1, an HLH transcription factor required for early neurogenesis (Wagner et al 2005). However, no effects on MASH1 transcription were observed, leading Wagner et al (2005) to hypothesize a post-transcriptional effect.…”

“…This may be particularly relevant, since a recent study demonstrated that deletion of the WT1(+KTS) isoform affected the expression of MASH1, an HLH transcription factor required for early neurogenesis (Wagner et al 2005). However, no effects on MASH1 transcription were observed, leading Wagner et al (2005) to hypothesize a post-transcriptional effect. Since the MASH1 gene, like the Id genes, contains a single small intron, it will be of interest to determine whether the effects of the +KTS protein on MASH1 expression are related to intron retention.…”

“…The +/−KTS isoform ratio is tightly regulated, and disruption of the ratio has been implicated in the pathogenesis of Frasier syndrome in humans and in mice (Barbaux et al 1997;Klamt et al 1998;Hammes et al 2001). Interestingly, a recent study has further highlighted the importance of the WT1(+KTS) isoform, by demonstrating that it is required for normal development of the olfactory system (Wagner et al 2005).…”