Esrom, an ortholog of PAM (protein associated with c-myc), regulates pteridine synthesis in the zebrafish.
Zebrafish esrom mutants have an unusual combination of phenotypes: in addition to a defect in the projection of retinal axons, they have reduced yellow pigmentation. Here, we investigate the pigment phenotype and, from this, provide evidence for an unexpected defect in retinal neurons. Esrom is not required for the differentiation of neural crest precursors into pigment cells, nor is it essential for cell migration, pigment granule biogenesis, or translocation. Instead, loss of yellow color is caused by a deficiency of sepiapterin, a yellow pteridine. The level of several other pteridines is also affected in mutants. Importantly, the cofactor tetrahydrobiopterin (BH4) is drastically reduced in esrom mutants. Mutant retinal neurons also appear deficient in this pteridine. BH4-synthesizing enzymes are active in mutants, indicating a defect in the regulation rather than production of enzymes. Esrom has recently been identified as an ortholog of PAM (protein associated with c-myc), a very large protein involved in synaptogenesis in Drosophila and C. elegans. These data thus introduce a new regulator of pteridine synthesis in a vertebrate and establish a function for the Esrom protein family outside synaptogenesis. They also raise the possibility that neuronal defects are due in part to an abnormality in pteridine synthesis.
Le Guyader
Sylvie
S
Developmental Neurobiology Group, Temasek Life Sciences Laboratory, Singapore 117604, Singapore.
Maier
Josef
J
Jesuthasan
Suresh
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002855:Chromatography, Thin Layer; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000201:enzymology / Q000648:ultrastructure; D015971:Gene Expression Regulation, Enzymologic; D008854:Microscopy, Electron; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010858:Pigmentation / Q000502:physiology*; D011622:Pterins / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D011622:Pterins; D029961:Zebrafish Proteins; C497200:mycbp2 protein, zebrafish; D001708:Biopterins; C016727:sepiapterin; D006899:Mixed Function Oxygenases; C003402:sapropterin