Saint-Marc, C. | Search bioRxiv

bioRxiv2023

Purine biosynthesis pathways are required for myogenesisin Xenopus laevis

Purines are required for fundamental biological processes and alterations in their metabolism lead to severe genetic diseases associated with developmental defects whose etiology remains unclear. Here, we studied the developmental requirements for purine metabolism using the amphibian Xenopus laevis as a vertebrate model. We provide the first functional characterization of purine pathway-genes and show that these genes are mostly expressed in nervous and muscular embryonic tissues. Morphants were generated to decipher the functions of these genes, with a focus on the adenylosuccinate lyase (ADSL), an enzyme required for both salvage and de novo purine pathways. adsl.L knock-down leads to severe reduction in the expression of the Myogenic Regulatory Factors (MRFs: Myod1, Myf5 and Myogenin), thus resulting in defects in somitogenesis and in the formation and/or migration of both craniofacial and hypaxial muscle progenitors. Similar alterations were observed upon reduced expression of hprt1.L and ppat, two genes specific to the salvage and the de novo pathways, respectively. In conclusion, our data shows for the first time that de novo and recycling purine pathways are essential for myogenesis and highlight new mechanisms in the regulation of MRFs gene expression.

developmental biology↗

bioRxiv2018

Adenylosuccinate Lyase activity in the Purine recycling pathway is essential for developmental timing, germline maintenance and muscle integrity in C. elegans.

Purine homeostasis is ensured through a metabolic network widely conserved from prokaryotes to humans. Purines can either be synthesized de novo, reused, or produced by interconversion of extant metabolites using the so-called recycling pathway. Although thoroughly characterized in microorganisms, such as yeast or bacteria, little is known about the regulation of this biosynthesis network in metazoans. In humans, several diseases are linked to purine biosynthesis deficiencies through yet poorly understood etiologies. Particularly, the deficiency in Adenylosuccinate Lyase (ADSL), one enzyme involved both in the purine de novo and recycling pathways, causes severe muscular and neuronal symptoms. In order to address the mechanisms underlying this deficiency, we established Caenorhabditis elegans as a metazoan model organism to study purine metabolism, while focusing on ADSL. We show that the purine biosynthesis network is functionally conserved in C. elegans. Moreover, ADSL is required for developmental timing and germline stem cell maintenance, and muscle integrity. Our results allow to ascribe developmental and tissue specific phenotypes to separable steps of the purine metabolic network in an animal model. Particularly, the muscle, germline and developmental defects are linked specifically to the ADSL role in the purine recycling pathway.

genetics↗