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Identification and Tissue-Specific Characterization of Novel SHOX-Regulated Genes in Zebrafish Highlights SOX Family Members Among Other Genes
Ist Teil von
Frontiers in genetics, 2021-05, Vol.12, p.688808-688808
Ort / Verlag
Frontiers Media S.A
Erscheinungsjahr
2021
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
SHOX
deficiency causes a spectrum of clinical phenotypes related to skeletal dysplasia and short stature, including Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome, and idiopathic short stature. SHOX controls chondrocyte proliferation and differentiation, bone maturation, and cellular growth arrest and apoptosis
via
transcriptional regulation of its direct target genes
NPPB
,
FGFR3
, and
CTGF
. However, our understanding of SHOX-related pathways is still incomplete. To elucidate the underlying molecular mechanisms and to better understand the broad phenotypic spectrum of
SHOX
deficiency, we aimed to identify novel SHOX targets. We analyzed differentially expressed genes in
SHOX
-overexpressing human fibroblasts (NHDF), and confirmed the known SHOX target genes
NPPB
and
FGFR
among the most strongly regulated genes, together with 143 novel candidates. Altogether, 23 genes were selected for further validation, first by whole-body characterization in developing
shox
-deficient zebrafish embryos, followed by tissue-specific expression analysis in three
shox
-expressing zebrafish tissues: head (including brain, pharyngeal arches, eye, and olfactory epithelium), heart, and pectoral fins. Most genes were physiologically relevant in the pectoral fins, while only few genes were also significantly regulated in head and heart tissue. Interestingly, multiple
sox
family members (
sox5
,
sox6
,
sox8
, and
sox18
) were significantly dysregulated in
shox
-deficient pectoral fins together with other genes (
nppa
,
nppc
,
cdkn1a
,
cdkn1ca
,
cyp26b1
, and
cy26c1
), highlighting an important role for these genes in
shox
-related growth disorders. Network-based analysis integrating data from the Ingenuity pathways revealed that most of these genes act in a common network. Our results provide novel insights into the genetic pathways and molecular events leading to the clinical manifestation of
SHOX
deficiency.