ArticleProceedings of the National Academy of Sciences of the United States of America2015
Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 72 citations in OpenAlex.
- Multiple gene knockouts in newts reveal novel functions of 5' Hox genes in limb development along the anterior-posterior and proximal-distal axes.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Article
- Genetic knockout suggests Isl1 enhancer redundancy in mouse hindlimb development.Developmental biology · 2025Article
- A de novo SALL4 mutation causes unilateral renal agenesis by misregulating genes involved in kidney development.Orphanet journal of rare diseases · 2025Article
- Thalidomide-induced limb malformations: an update and reevaluation.Archives of toxicology · 2025Review
- METTL14 regulates chondrogenesis through the GDF5-RUNX-extracellular matrix gene axis during limb development.Nature communications · 2025Article
- Review
- Molecular mechanism, diagnosis, and treatment of VACTERL association.Frontiers in pediatrics · 2025Review
- Identification of Pappa and Sall3 as Gli3 direct target genes acting downstream of cilia signaling in corticogenesis.Cerebral cortex (New York, N.Y. : 1991) · 2024Article
- Sall4 regulates downstream patterning genes during limb regeneration.Developmental biology · 2024Article
- TBX3 is essential for establishment of the posterior boundary of anterior genes and upregulation of posterior genes together with HAND2 during the onset of limb bud development.Development (Cambridge, England) · 2024Article
- Sall genes regulate hindlimb initiation in mouse embryos.Genetics · 2024Article
- Sall4 regulates posterior trunk mesoderm development by promoting mesodermal gene expression and repressing neural genes in the mesoderm.Development (Cambridge, England) · 2024Article
- Direct reprogramming of non-limb fibroblasts to cells with properties of limb progenitors.Developmental cell · 2024Article
- Integrative Role of the SALL4 Gene: From Thalidomide Embryopathy to Genetic Defects of the Upper Limb, Internal Organs, Cerebral Midline, and Pituitary.Hormone research in paediatrics · 2024Review
- Cereblon influences the timing of muscle differentiation inProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Sall4 restricts glycolytic metabolism in limb buds through transcriptional regulation of glycolytic enzyme genes.Developmental biology · 2023Article
- Hyperplastic Human Macromass Cartilage for Joint Regeneration.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Identification of SALL4 Expressing Islet-1+ Cardiovascular Progenitor Cell Clones.International journal of molecular sciences · 2023Article
- How might we build limbsFrontiers in cell and developmental biology · 2023Review
- Etv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud.Nature communications · 2022Article
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Authors and funding
6 authors at 4 institutions in 4 countries.
Funding
Abstract
Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.
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