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Mol Endocrinol. 2012 Jun;26(6):1014-27.
The HMG-box transcription factor Sox4b is required
for pituitary expression of gata2a and specifcation
of thyrotrope and gonadotrope cells in zebrafsh.
Quiroz Y, Lopez M, Mavropoulos A, Motte P, Martial JA, Hammerschmidt M, Muller M.
Abstract
The pituitary is a complex gland comprising diferent cell types each secreting specifc
hormones. The extensive network of signaling molecules and transcription factors required
for determination and terminal diferentiation of specifc cell types is still not fully unders-
tood. The SRY-like HMG-box (SOX) transcription factor Sox4 plays important roles in many
developmental processes and has two homologs in zebrafsh, Sox4a and Sox4b. We show that
the sox4b gene is expressed in the pituitary anlagen starting at 24h after fertilization (hpf)
and later in the entire head region including the pituitary. At 48 hpf, sox4b mRNA colocalizes
with that for TSH (tshβ), glycoprotein subunit α (gsuα), and the Zn fnger transcription factor
Gata2a. Loss of Sox4b function, using morpholino knockdown or expression of a dominant-
negative Sox4 mutant, leads to a drastic decrease in tshβ and gsuα expression and reduced
levels of gh, whereas other anterior pituitary gland markers including prl, slβ, pomc, and lim3
are not afected. Sox4b is also required for expression of gata2a in the pituitary. Knockdown
of gata2a leads to decreased tshβ and gsuα expression at 48 hpf, similar to sox4b morphants.
Injection of gata2a mRNA into sox4b morphants rescued tshβ and gsuα expression in thyro-
trope cells. Finally, sox4b or gata2a knockdown causes a signifcant decrease of gonadotropin
expression (lhβ and fshβ) at 4 d after fertilization. In summary, our results indicate that Sox4b
is expressed in zebrafsh during pituitary development and plays a crucial role in the diferen-
tiation of thyrotrope and gonadotrope cells through induction of gata2a expression in the
developing pituitary.
PLoS One. 2012;7(10):e46425.
In vivo tumorigenesis was observed after injection
of in vitro expanded neural crest stem cells isolated
from adult bone marrow.
Wislet-Gendebien S, Poulet C, Neirinckx V, Hennuy B, Swingland JT, Laudet E, Sommer L,
Shakova O, Bours V, Rogister B.
Abstract
Bone marrow stromal cells are adult multipotent cells that represent an attractive tool in
cellular therapy strategies. Several studies have reported that
in vitro
passaging of mesen-
chymal stem cells alters the functional and biological properties of those cells, leading to the
accumulation of genetic aberrations. Recent studies described bone marrow stromal cells
(BMSC) as mixed populations of cells including mesenchymal (MSC) and neural crest stem cells
(NCSC). Here, we report the transformation of NCSC into tumorigenic cells, after
in vitro
long-term passaging. Indeed, the characterization of 6 neural crest-derived clones revealed
the presence of one tumorigenic clone. Transcriptomic analyses of this clone highlighted,
among others, numerous cell cycle checkpoint modifcations and chromosome 11q down-
regulation (suggesting a deletion of chromosome 11q) compared with the other clones.
Moreover, unsupervised analysis such as a dendrogram generated after agglomerative
hierarchical clustering comparing several transcriptomic data showed important simila-
rities between the tumorigenic neural crest-derived clone and mammary tumor cell lines.
Altogether, it appeared that NCSC isolated from adult bone marrow represents a potential
danger for cellular therapy, and consequently, we recommend that phenotypic, functional
and genetic assays should be performed on bone marrow mesenchymal and neural crest stem
cells before in vivo use, to demonstrate whether their biological properties, after
ex vivo
expansion, remain suitable for clinical application.