Abstract
Sall4 encodes a transcription factor and is known to participate in the pluripotency network of embryonic stem cells. Sall4 expression is known to be high in early stage post-implantation mouse embryos. During early post-gastrulation stages, Sall4 is highly expressed in the tail bud and distal limb buds, where progenitor cells are maintained in an undifferentiated status. The expression of Sall4 is rapidly downregulated during embryonic development. We previously demonstrated that Sall4 is required for limb and posterior axial skeleton development by conditional deletion of Sall4 in the T (Brachyury) lineage. To gain insight into Sall4 functions in embryonic development and postnatal digit regeneration, we genetically overexpressed Sall4 in the mesodermal lineage by the TCre transgene and a novel knockin allele of Rosa26-loxP-stop-loxP-Sall4. In significant contrast to severe defects by Sall4 loss of function reported in previous studies, overexpression of Sall4 resulted in normal morphology and pattern in embryos and neonates. The length of limb long bones showed subtle reduction in Sall4-overexpression mice. It is known that the digit tip of neonatal mice has level-specific regenerative ability after experimental amputation. We observed Sall4 expression in the digit tip by using a sensitive Sall4-LacZ knock-in reporter expression. Sall4 overexpression did not alter the regenerative ability of the terminal phalange that normally regenerates after amputation. Moreover, Sall4 overexpression did not confer regenerative ability to the second phalange that normally does not regenerate after amputation. These genetic experiments show that overexpression of Sall4 does not alter the development of the appendicular and axial skeleton, or neonatal digit regeneration. The results suggest that Sall4 acts as a permissive factor rather than playing an instructive role.
Original language | English (US) |
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Article number | e0267273 |
Journal | PloS one |
Volume | 17 |
Issue number | 4 April |
DOIs | |
State | Published - Apr 2022 |
Bibliographical note
Funding Information:This study was supported by a grant from the National Institutes of Health (https://www. nih.gov) to YK (R01AR064195). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to Sandy Zhang for her excellent technical assistance. We are also grateful to Dr. David Zarkower for sharing materials to generate the R26-Sall4 mouse line, to the University of Minnesota Cytogenomics Laboratory and the Mouse Genetics Laboratory for their excellent service in karyotyping and chimera production, respectively. KQC, AA and JK were partially supported by the University of Minnesota?s Undergraduate Research Opportunity Program.
Publisher Copyright:
Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords
- Animals
- DNA-Binding Proteins/genetics
- Embryonic Development/genetics
- Embryonic Stem Cells
- Female
- Mice
- Pregnancy
- Stem Cell Factor
- Transcription Factors/genetics
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural