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

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

[20]

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

[35]

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

[36]

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

[44]

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]