TY - JOUR
T1 - The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms
AU - Traustadóttir, Gunnhildur Ásta
AU - Lagoni, Lene Vig
AU - Ankerstjerne, Lea Bo Sønderlund
AU - Bisgaard, Hanne Cathrine
AU - Jensen, Charlotte Harken
AU - Andersen, Ditte Caroline
PY - 2019/4
Y1 - 2019/4
N2 - Delta like non-canonical Notch ligand 1 (Dlk1) is an imprinted gene, mainly known for its involvement in adipogenesis, although it has been associated with many other stem cells/progenitors and is known to be widely expressed during organism development and tissue regeneration. In a systematic manner, we have outlined the overall expression pattern of Dlk1 in both man and mouse, and found Dlk1 to be expressed in tissues from all three germ layers. Yet, Dlk1 expression decreases along with increased differentiation as gestation proceeds and in most tissues Dlk1 is absent around birth. Thus, in adults, expression of Dlk1 is restricted to a few tissues and progenitor cells, but is re-expressed during disease and regeneration. Although diffferences exist, we found an overall conservation of Dlk1 expression between mouse and man, and conclude in that sense that the mouse is an appropiate model to study Dlk1. In agreement with the observed Dlk1 expression pattern, we found that the majority of published Dlk1 studies, report Dlk1 to have an inhibitory effect on both cell proliferation and differentiation, but the levels of the different DLK1 isoforms may be critical and have an impact on the overall outcome. This may also be an issue during tissue regeneration where several studies have reported Dlk1′s impact during skeletal muscle and liver regeneration without establishing the exact role. Likewise, the underlying mechanism of Dlk1 action is unknown, and seems to depend on both Notch dependent and independent pathways. However, from our data it is intriguing to speculate that the actual role of DLK1 may be to function as a checkpoint to slow down proliferation while forcing cells into the process of differentiation, and thus switch the cell/organ to a state of growth and hypertrophy. This may fit well with its reported impact on growth restiction and body size. Thus, our study which for the first time summarizes reported knowledge on Dlk1 in tissue development and regeneration as well as on the Dlk1 mechanism may provide novel insight to the general role of this remarkable imprinted gene in controlling cell growth, from which new hypotheses can be made in the field of stem cell biology and regenerative medicine.
AB - Delta like non-canonical Notch ligand 1 (Dlk1) is an imprinted gene, mainly known for its involvement in adipogenesis, although it has been associated with many other stem cells/progenitors and is known to be widely expressed during organism development and tissue regeneration. In a systematic manner, we have outlined the overall expression pattern of Dlk1 in both man and mouse, and found Dlk1 to be expressed in tissues from all three germ layers. Yet, Dlk1 expression decreases along with increased differentiation as gestation proceeds and in most tissues Dlk1 is absent around birth. Thus, in adults, expression of Dlk1 is restricted to a few tissues and progenitor cells, but is re-expressed during disease and regeneration. Although diffferences exist, we found an overall conservation of Dlk1 expression between mouse and man, and conclude in that sense that the mouse is an appropiate model to study Dlk1. In agreement with the observed Dlk1 expression pattern, we found that the majority of published Dlk1 studies, report Dlk1 to have an inhibitory effect on both cell proliferation and differentiation, but the levels of the different DLK1 isoforms may be critical and have an impact on the overall outcome. This may also be an issue during tissue regeneration where several studies have reported Dlk1′s impact during skeletal muscle and liver regeneration without establishing the exact role. Likewise, the underlying mechanism of Dlk1 action is unknown, and seems to depend on both Notch dependent and independent pathways. However, from our data it is intriguing to speculate that the actual role of DLK1 may be to function as a checkpoint to slow down proliferation while forcing cells into the process of differentiation, and thus switch the cell/organ to a state of growth and hypertrophy. This may fit well with its reported impact on growth restiction and body size. Thus, our study which for the first time summarizes reported knowledge on Dlk1 in tissue development and regeneration as well as on the Dlk1 mechanism may provide novel insight to the general role of this remarkable imprinted gene in controlling cell growth, from which new hypotheses can be made in the field of stem cell biology and regenerative medicine.
KW - Delta like non-canonical Notch ligand 1
KW - Differentiation
KW - Mammalian development
KW - Proliferation
KW - Regenerative medicine
KW - Stem cell biology
U2 - 10.1016/j.cytogfr.2019.03.006
DO - 10.1016/j.cytogfr.2019.03.006
M3 - Review
C2 - 30930082
AN - SCOPUS:85063490023
SN - 1359-6101
JO - Cytokine and Growth Factor Reviews
JF - Cytokine and Growth Factor Reviews
ER -