PT  - JOURNAL ARTICLE
AU  - Zachary M. Collins
AU  - Kana Ishimatsu
AU  - Tony Y.C. Tsai
AU  - Sean G. Megason
TI  - A Scube2-Shh feedback loop links morphogen release to morphogen signaling to enable scale invariant patterning of the ventral neural tube
AID  - 10.1101/469239
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 469239
4099  - http://biorxiv.org/content/early/2018/11/13/469239.short
4100  - http://biorxiv.org/content/early/2018/11/13/469239.full
AB  - To enable robust patterning, morphogen systems should be resistant to variations in gene expression and tissue size. Here we explore how a Shh morphogen gradient in the ventral neural tube enables proportional patterning in embryos of varying sizes. Using a surgical technique to reduce the size of zebrafish embryos and quantitative confocal microscopy, we find that patterning of neural progenitors remains proportional after size reduction. Intriguingly, a protein necessary for Shh release, Scube2, is expressed far from the source of sonic hedgehog production. scube2 expression levels control Shh signaling extent during ventral neural patterning and conversely Shh signaling represses the expression of scube2, thereby restricting its own signaling. scube2 is disproportionately downregulated in size-reduced embryos, providing a potential mechanism for size-dependent regulation of Shh. This regulatory feedback is necessary for pattern scaling, as demonstrated by a loss of scaling in scube2 overexpressing embryos. In a manner akin to the expander-repressor model of morphogen scaling, we conclude that feedback between Shh signaling and scube2 expression enables proportional patterning in the ventral neural tube by encoding a tissue size dependent morphogen signaling gradient.Summary Statement The Shh morphogen gradient can scale to different size tissues by feedback between Scube2 mediated release of Shh and Shh based inhibition of Scube2 expressionAuthor Contributions Z.M.C. conducted experiments and data analysis. Z.M.C and S.G.M. conceived the study, designed the experiments, and wrote the paper. K.I and Z.M.C. developed the size reduction technique. T.Y.C.T helped develop the image analysis technique and generated the tg(shha:memCherry) reporter line. S.G.M. supervised the overall study.