Biology subjects

Lopez-Delgado, A. C.

Publications and source records attributed to Lopez-Delgado, A. C..

3 recordsLinked to original sources

bioRxiv2025

Differential fates of vertebrate Kazald gene quartet, from ancestral roles in skeletogenesis and regeneration to putative innovations in fish and birds

Salamanders are known for their incredible regenerative abilities, but translating findings to mammals is complicated by unannotated genes and unclear orthology. An example highlighting this difficulty was a discovery in the axolotl (Ambystoma mexicanum) of a regeneration-associated gene that has been identified as either Kazald1 or Kazald2. Since orthology inference of genes across species is crucial to identifying gains and losses of gene functions, and thus if gene usage is likely to be consistent across species, we investigated the evolution of the axolotl genes using an extensive cross-species analysis. Molecular phylogeny inference conclusively identified the regeneration-associated gene as Kazald2, but also revealed an undescribed four-member Kazald gene family in jawed vertebrates. Moreover, synteny comparisons demonstrated that this family originated in the ancestral two-rounds of whole genome duplication. Additionally, we performed vertebrate-wide comparisons of Kazald gene expression profiles, employing available RNA-Seq which we validated in whole tissues of axolotl, zebrafish, and sharks. This uncovered seemingly ancestral connections conserved over jawed vertebrate evolution, such as Kazald1 with skeletogenesis and odontogenesis and Kazald2 with regeneration. It also suggested novel putative roles within specific lineages, including Kazald3 in teleost fish skeletogenesis and Kazald4 within avian brains. Our study thus demonstrates the establishment of a Kazald gene quartet in the jawed vertebrate ancestor, and elucidates the asymmetry of gene fates of its members, including deeply ancestral roles and comparably recent innovations. This provides a comprehensive report of this formerly undescribed gene family, offering a solid foundation for future studies of these genes in diverse species.

evolutionary biology↗

bioRxiv2023

Compartmentalization and synergy of osteoblasts drive bone formation in the regenerating fin

Zebrafish faithfully regenerate their fins after amputation which includes restoration of bone tissue and a component of cell plasticity. It is currently unclear how different cell populations of the regenerate divide labor to allow for efficient regenerate growth and proper patterning. Here, we studied lineage relationships of FACS-enriched epidermal, blastemal and bone forming fin regenerate cells by single cell (sc) RNA sequencing, lineage tracing, targeted osteoblast ablation and electron microscopy to show that the majority of osteoblasts in the outgrowing regenerate derive from osterix+ osteoblasts, while mmp9+ cells give rise to a limited cell number at the fin segment joints. A third population of distal blastema cells contributes to distal osteoblast progenitors, suggesting compartmentalization during appendage regeneration. Fin elongation and bone formation are carried out by distinct regenerate cell populations, and these variably depend on Fgf signaling. Ablation of osterix+ osteoblasts irreversibly impairs patterning of segment joints, and prevents bone matrix formation in the proximal regenerate. The resulting reduced regenerate length is partially compensated for by the distal regenerate which shows increased Wnt signaling activity. Surprisingly, ablation of joint cells does not abolish the formation of segment joints. Our study characterizes rare fin regenerate cell populations, indicates intricate osteoblast-blastema lineage relationships, inherent detection and compensation of impaired regeneration, and demonstrates zonation of the elongating regenerate. Furthermore, it sheds light on the variable dependence of bone formation on growth factor signaling.

developmental biology↗

bioRxiv2020

Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription factors and retinoic acid

Vertebrate axial skeletal patterning is controlled by coordinated collinear expression of Hox genes and axial level-dependent activity of Hox protein combinations. Transcription factors of the Meis family act as cofactors of Hox proteins and profusely bind to Hox complex DNA, however their roles in mammalian axial patterning have not been established. Similarly, retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors, however, whether this role is related to Meis/Hox activity in axial patterning remains unknown. Here we study the role of Meis in axial skeleton formation and its relationship to the RA pathway by characterizing Meis1, Meis2 and Raldh2 mutant mice. Meis elimination produces axial skeleton defects without affecting Hox gene transcription, including vertebral homeotic transformations and rib mis-patterning associated to defects in the hypaxial myotome. While Raldh2 and Meis positively regulate each other, Raldh2 elimination largely recapitulates the defects associated to Meis-deficiency and Meis overexpression rescues the axial skeletal defects in Raldh2 mutants. We propose a Meis-RA positive feedback loop whose output is Meis levels and is essential to establish anterior-posterior identities and pattern of the vertebrate axial skeleton.

developmental biology↗