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Table 2 The role of ATF6 in the development of diverse tissues and organs

From: A lifetime of stress: ATF6 in development and homeostasis

Tissue Intervention/Observation Effect/Comment Reference(s)
Bone and Cartilage OE of ATF6 in foetal mouse metatarsals ex vivo as well as C3H10T1/2 and ATDC5 cells in vitro Enhanced chondrocyte hypertrophy, mineralisation, and endochondral bone growth in metatarsals and enhanced chondrocyte differentiation in vitro [17,18,19]
KD of ATF6 in C3H10T1/2 and ATDC5 cells (adenoviral siRNA delivery system) KD➔Inhibition of chondrocyte differentiation and hypertrophy
KD of ATF6α in murine bone marrow stromal cells and C3H10T1/2 cells BMP2➔RunX2➔ATF6➔osteocalcin
MC3T3-E1 + MTA
ATF6 KD in MTA-treated cells
MTA stimulated osteoblastic differentiation via upregulation of osteocalcin
ATF6 KD abrogated MTA-induced mineralisation
OE of ATF6 in human dental pulp cells Matrix mineralisation and odontoblastic differentiation increased [21]
Ocular Tissue Immunofluorescent staining of ATF6 expression in the embryonic eye lens (FVB/N-Har mice) ATF6 expression and cleavage were detected in lens fibre cells in the developing mouse embryo [24]
Homozygosity mapping, linkage analyses and exome sequencing in patients with achromatopsia (ACHM) Patients with ACHM displayed ATF6 mutations, which severely compromise ATF6 function. Patients also exhibited foveal deficits, suggesting that ATF6 plays a crucial role in the development of the fovea and cone photoreceptors in humans [25,26,27]
Early-onset photoreceptor degeneration ATF6 splice-variant mutations causing compromised photoreceptor function
Nervous tissue Western blot analyses of glycosylated ATF6 expression in adult and embryonic mouse brains Compared to adult tissue, the expression of partially glycosylated ATF6 is elevated in the brains of mouse embryos [30]
Olfactory sensory neurons Low-level expression (relative to ATF5) of ATF6 during development [32]
Immunohistochemical staining of ATF6 (cytoplasmic and nuclear) in the developing rat cerebellum ATF6 was activated at postnatal day 7 (prior to the appearance of myelin), with maximal nuclear-localised ATF6 visualised at postnatal day 10 (onset of myelination) [33]
Muscle OE of active ATF6 in myoblasts ↑ ATF6 ➔ ↓ Mcl-1 ➔ apoptotic myoblast cells.
ATF6 may regulate muscle cell development through promoting post-translational modification of Mcl-1
OE of DKK3 in mESCs
Transient ATF6 overexpression or siRNA-mediated ATF6 KD at day 2 of ESC differentiation
DKK3 induced differentiation of ESCs into smooth muscle cells (SMCs)
↑ ATF6 during DKK3-induced ESC-SMC differentiation
OE and KD ➔ ATF6 is involved in DKK3-mediated SMC generation
via ↑myocardin expression
Ovarian Tissue Analyses of ATF6 and associated markers during the bovine corpus luteum lifespan and in goat granulosa ATF6 and ATF4➔ ↑CHOP and ↑caspase-12 [37,38,39]
Molecular and immunohistochemical detection of ATF6α during peri-implantation and the oestrous cycle in mice ↑ATF6α mRNA and protein in the d5 uterus close to the implantation site and in d7–8 secondary decidual zone; ATF6α expression affected by progesterone and estrogen in ovariectomised mice [40]
Adipose Tissue KD of ATF6α in C3H10T1/2 cells ATF6α KD ➔ ↓ C3H10T1/2 differentiation and ↓ lipid accumulation [41]
Glucose deprivation ↓SREBP2-mediated lipogenesis [42]
Adipogenesis in salmon and rainbow trout ATF6/ATF6β upregulated during adipogenesis [14, 43]
OE and KD in pre-adipocytic 3 T3-L1 cells ATF6 OE ➔ ↑TIS7 in 3T3-L1 cells
ATF6KD under hypoxia➔↑AP-2 in pre-adipocytes;
ATF6 KD ↓ hypoxia-induced ↑TIS7 and ↓adipogenic gene expression
Early Stem Cell/Mesoderm Small molecule ATF6 activation in human ESCs ATF6 activation suppressed pluripotency, enhanced stem cell differentiation and steered cells towards mesodermal fate [28]
  1. Key: ACHM achromatopsia, ATF6 activating transcription factor 6, CHOP C/EBP homologous protein, ESC embryonic stem cell, KD knockdown, KO knockout, MCL-1 myeloid cell leukaemia sequence 1, MTA mineral trioxide aggregate, OE over-expression, PCR polymerase chain reaction, RunX2 runt-related transcription factor 2, SMC smooth muscle cell, SREBP-2 sterol regulatory element binding protein 2, TIS7 tetradecanoyl phorbol acetate induced sequence 7