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Hedgehog signaling enables nutrition-responsive inhibition of an alternative morph in a polyphenic beetle.

ABSTRACT: The recruitment of modular developmental genetic components into new developmental contexts has been proposed as a central mechanism enabling the origin of novel traits and trait functions without necessitating the origin of novel pathways. Here, we investigate the function of the hedgehog (Hh) signaling pathway, a highly conserved pathway best understood for its role in patterning anterior/posterior (A/P) polarity of diverse traits, in the developmental evolution of beetle horns, an evolutionary novelty, and horn polyphenisms, a highly derived form of environment-responsive trait induction. We show that interactions among pathway members are conserved during development of Onthophagus horned beetles and have retained the ability to regulate A/P polarity in traditional appendages, such as legs. At the same time, the Hh signaling pathway has acquired a novel and highly unusual role in the nutrition-dependent regulation of horn polyphenisms by actively suppressing horn formation in low-nutrition males. Down-regulation of Hh signaling lifts this inhibition and returns a highly derived sigmoid horn body size allometry to its presumed ancestral, linear state. Our results suggest that recruitment of the Hh signaling pathway may have been a key step in the evolution of trait thresholds, such as those involved in horn polyphenisms and the corresponding origin of alternative phenotypes and complex allometries.

SUBMITTER: Kijimoto T

PROVIDER: S-EPMC4889385 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Project description:Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor of many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling profoundly depend on interactions with other pathways such as epidermal growth factor receptor-mediated signaling which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. We demonstrate that the human medulloblastoma cell line Daoy possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic Hedgehog or Smoothened agonist induced expression of GLI1 protein and prevented processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed on the transcriptomic as well as proteomic level. Daoy cells responded to the co-treatment by downregulating GLI1, PTCH, and HHIP on the transcript level which was also seen when Amphiregulin (AREG) was used instead of EGF. The finding that EGFR signaling silences proteins acting as negative regulators of HH signaling is firstly described here as a novel crosstalk mechanism. Furthermore, combined EGFR/HH signaling maintains high GLI1 protein levels contrasting its downregulation on the transcript level. On the other hand, high level synergism was observed with respect to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile pointing to more wide-spread, yet context-dependent, interactions between HH/GLI and growth factor receptor signaling in human malignancies. To study interactions between HH- and EGF-induced signaling, time-resolved measurements were carried out over a period of 24 h at 14 different time points after stimulation by EGF with and without additional stimulation by SHH. Furthermore, as a control, cells without any stimulation by EGF and SHH (control) and cells in the presents of SHH were analyzed. Overall, three biological replicates of 60 different treatment/timepoints were analyzed yielding 180 different samples.

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Hedgehog signaling enables nutrition-responsive inhibition of an alternative morph in a polyphenic beetle.

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