Sall4 Is Essential for Stabilization, But Not for Pluripotency, of Embryonic Stem Cells by Repressing Aberrant Trophectoderm Gene Expression

Abstract

Sall4 is a mouse homolog of a causative gene of the autosomal dominant disorder Okihiro syndrome. We previously showed that the absence of Sall4 leads to lethality during peri-implantation and that Sall4-null embryonic stem (ES) cells proliferate poorly with intact pluripotency when cultured on feeder cells. Here, we report that, in the absence of feeder cells, Sall4-null ES cells express the trophectoderm marker Cdx2, but are maintained for a long period in an undifferentiated state with minimally affected Oct3/4 expression. Feeder-free Sall4-null ES cells contribute solely to the inner cell mass and epiblast in vivo, indicating that these cells still retain pluripotency and do not fully commit to the trophectoderm. These phenotypes could arise from derepression of the Cdx2 promoter, which is normally suppressed by Sall4 and the Mi2/NuRD HDAC complex. However, proliferation was impaired and G1 phase prolonged in the absence of Sall4, suggesting another role for Sall4 in cell cycle control. Although Sall1, also a Sall family gene, is known to genetically interact with Sall4 in vivo, Sall1-null ES cells have no apparent defects and no exacerbation is observed in ES cells lacking both Sall1 and Sall4, compared with Sall4-null cells. This suggests a unique role for Sall4 in ES cells. Thus, though Sall4 does not contribute to the central machinery of the pluripotency, it stabilizes ES cells by repressing aberrant trophectoderm gene expression. Disclosure of potential conflicts of interest is found at the end of this article.

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“…SALL4, a member of the spalt family, is a homeotic gene originally identified in Drosophila as a transcription factor required for development (Frei et al, 1988). Having essential roles in development in mammals, SALL4 is vital for the maintenance of pluripotency, self-renewal, efficient proliferation/stabilization, and cell fate decision of ESCs (Elling et al, 2006;Zhang et al, 2006;Yuri et al, 2009). SALL4 is also involved in the maintenance of human adult stem cell properties (Yang et al, 2010).…”

“…Structural properties of human SALL consist of several C2H2 zinc finger domains that can bind DNA and in some cases RNA and proteins (Kohlhase et al, 2002a). In embryonic stem cells (ESCs), SALL4 has significant roles in the maintenance of pluripotency and self-renewal, efficient proliferation/ stabilization, and cell fate decision Yuri et al, 2009). It is also engaged in the maintenance of human adult stem cell features (Yang et al, 2010).…”

Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

“…The mouse lines for Sall4 (15,40), Gli3 (41), Tcre (21), Hoxb6Cre (22), and Prx1Cre (24) were maintained on a mixed genetic background. Skeletal preparation was done as published (42).…”

Members of the NODE (Nanog and Oct4-associated deacetylase) complex and SOX-2 promote the initiation of a natural cellular reprogramming event in vivo

“…The NODE complex notably contains OCT4 and SALL4, known interaction partners of Nanog (3), as well as MTA1/2 (4). SALL4, a zinc finger transcription factor, has been shown to stabilize ES cell self-renewal and to enhance iPS reprogramming (4)(5)(6)(7)(8)(9). MTA1 is a transcriptional modulator and appears to have an important role in cellular identity as its expression has been correlated with invasive cancers and metastasis (10) and as loss of MTA1 in ES cells impairs their pluripotency (4).…”