PgmNr Z604: Glycolysis meets Fgf signaling: The glycolytic enzyme PGK1 is required non-autonomously for Fgf-dependent specification of otic neurons in zebrafish.

Authors:
B. B. Riley; H. Kantarci; K. Hofstetter


Institutes
Texas A&M University, College Station, TX.


Abstract:

We conducted a pilot screen in zebrafish to identify ENU-point mutations that alter production of neurons of the statoacoustic ganglion (SAG), which innervates the inner ear.  Two SAG-deficient mutations were recovered, termed sagd1 and sagd2.  Both are recessive lethal mutations that show no overt morphological defects but both strongly reduce subsets of SAG neurons.  sagd1 mutants, for example, show a specific deficiency in vestibular neurons required for balance, whereas auditory neurons develop normally.  Whole-genome sequencing revealed that sagd1 affects the glycolytic enzyme Pgk1 (Phosphoglycerate kinase-1).  Targeted disruption of pgk1 using CRISPRs yields an identical phenotype.  Surprisingly, it appears that Pgk1 acts non-autonomously to promote efficient Fgf signaling.  Fgf is normally required for specification of SAG neuroblasts, with vestibular neuroblasts forming first, followed by auditory neuroblasts.  Although expression of known Fgf ligands appears normal in sagd1 mutants, analysis of Fgf-reporters shows that the early phase of Fgf signaling required for vestibular neuroblasts is impaired.  Fgf signaling later recovers to support normal development of auditory neuroblasts.  Analysis of genetic mosaics shows the requirement for Pgk1 is non-cell autonomous, suggesting that Pgk1 acts outside the cell to facilitate Fgf’s role in SAG specification.  Other recent studies have shown that Pgk1 is often secreted to perform various “moonlighting” functions required for normal development, as well as for efficient metastasis of certain aggressive forms of cancer.  Because misexpression of Fgf8 from an inducible transgene does not rescue the sagd1 phenotype, we speculate that secreted Pgk1 directly or indirectly modifies the extracellular matrix to promote efficient Fgf signaling. Experiments are ongoing to determine how Pgk1 influences the Fgf pathway.



ZFIN Genetics Index
1. pgk1