{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:02:05Z","timestamp":1789970525792,"version":"4.0.1"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Retinoic acid (RA) plays a plethora of functions during embryonic development as well as post-natal life. In particular, RA function during limb development is associated with interdigital cell death. However, the molecular mechanism(s) through which RA signaling contributes to interdigital cell death remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To gain insights into the mechanism(s) involved, we used a conditional approach to inactivate the RA catalyzing enzyme Aldh1a2 thereby abrogating RA signaling in the distal limb.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and Discussion<\/jats:title>\n                    <jats:p>\n                      Our data first show that\n                      <jats:italic>Aldh1a2<\/jats:italic>\n                      mutant limb buds are characterized by a lack of apoptosis in the interdigital region, which results in a very severe syndactyly phenotype at birth. Molecular analysis of\n                      <jats:italic>Aldh1a2<\/jats:italic>\n                      mutant distal limb buds reveals that RA regulates the expression of several key genes in the interdigital tissue related to apoptosis in the limb and to the extracellular matrix degradation. The decreased expression of these genes in\n                      <jats:italic>Aldh1a2<\/jats:italic>\n                      mutant limb buds correlates with a decreased activity of their putative regulatory elements bound by the retinoic acid receptors supporting that these genes are possibly direct RA targets. We also identified mild skeletal defects in\n                      <jats:italic>Aldh1a2<\/jats:italic>\n                      conditional mutant, as newborns have smaller digits. This latter phenotype is associated with the decreased expression of genes important for chondrocytes differentiation and proliferation, notably\n                      <jats:italic>Ihh<\/jats:italic>\n                      ,\n                      <jats:italic>Foxc2<\/jats:italic>\n                      and\n                      <jats:italic>Igf1<\/jats:italic>\n                      . Finally, we show that the distal expression of\n                      <jats:italic>Aldh1a2<\/jats:italic>\n                      likely relies on the function of\n                      <jats:italic>Hoxa13<\/jats:italic>\n                      and\n                      <jats:italic>Hoxd13<\/jats:italic>\n                      establishing a potential cascade of molecular events responsible for the interdigit tissue regression.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1913173","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:35:27Z","timestamp":1789968927000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular analysis of Aldh1a2 conditional inactivation in developing limbs reveals mechanisms of retinoic-acid mediated interdigital apoptosis"],"prefix":"10.3389","volume":"14","author":[{"given":"Rodrigue","family":"Peraldi","sequence":"first","affiliation":[{"name":"Genetics and Development Research Unit, Institut de Recherches Cliniques de Montr\u00e9al","place":["Montr\u00e9al, QC, Canada"]},{"name":"D\u00e9partement de M\u00e9decine (Programme de Biologie Mol\u00e9culaire), Universit\u00e9 de Montr\u00e9al","place":["Montr\u00e9al, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yacine","family":"Kherdjemil","sequence":"additional","affiliation":[{"name":"Plateforme Mod\u00e9lisation des Maladies et \u00e9dition Du G\u00e9nome, Institut de Recherches Cliniques de Montr\u00e9al","place":["Montr\u00e9al, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Villiard","sequence":"additional","affiliation":[{"name":"Genetics and Development Research Unit, Institut de Recherches Cliniques de Montr\u00e9al","place":["Montr\u00e9al, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayuta","family":"Yakushiji-Kaminatsui","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS)","place":["Yokohama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Kmita","sequence":"additional","affiliation":[{"name":"Genetics and Development Research Unit, Institut de Recherches Cliniques de Montr\u00e9al","place":["Montr\u00e9al, QC, Canada"]},{"name":"D\u00e9partement de M\u00e9decine (Programme de Biologie Mol\u00e9culaire), Universit\u00e9 de Montr\u00e9al","place":["Montr\u00e9al, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2813","DOI":"10.1101\/gad.1017802","article-title":"The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6","volume":"16","author":"Akiyama","year":"2002","journal-title":"Genes Dev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1038\/ncb3250","article-title":"Integrin endosomal signalling suppresses anoikis","volume":"17","author":"Alanko","year":"2015","journal-title":"Nat. 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