dc.contributor.author
Geng, Shuang
dc.date.accessioned
2023-10-02T08:26:37Z
dc.date.available
2023-10-02T08:26:37Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/40936
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-40657
dc.description.abstract
During early forebrain development, the establishment of the regional identity of neural
progenitor cells (NPCs) relies on the integration of signals from multiple signaling
centers, including the WNT signaling pathway. WNT pathway is essential for
embryonic development and is regulated by LDL receptor related proteins (LRPs),
which act as co-receptors of frizzled. While the LRP family member - LRP5 and LRP6
are well known as co-receptors of frizzled, acting as the main receptor of WNT3a.
Recent evidence suggests that LRP4 also plays a role in the central nervous system.
My aim is to shed light on the common and distinct functions of LRP4 and LRP6 and
the interactions between LRP4/6 linked to the WNT pathway during early forebrain
development. To achieve this, a genetic approach was used to analyze the forebrain
development of LRP4-, LRP6-deficient mouse embryos, as well as Lrp4-/-; Lrp6-/-
double mutant mouse embryos at E9.5. High-resolution immunofluorescence imaging,
cell culture models and molecular biology approaches were employed to investigate
the effects of genetic inactivation of LRP4 and LRP6 on canonical WNT activity, mitotic
activity of forebrain neuronal precursors, and the development of NTDs.
The results of this study indicate that loss of LRP6 can lead to a developmental
disorder in E9.5 embryos, such as caudal truncation, neural tube defects (NTDs) and
forebrain hypoplasia. Importantly, loss of LRP4 can partially rescue these deficits in
Lrp6 null mutants. Specially, caudal truncation and impaired mitotic activity of forebrain
neuronal precursors observed in Lrp6-/- mutants were rescued in Lrp4-/-; Lrp6-/- double
mutants. However, cranial NTDs in LRP6-deficient mice were not ameliorated by
genetic ablation of Lrp4. Additionally, it was demonstrated that genetic inactivation of
LRP4 rescued impaired canonical WNT activity and the downstream targets in Lrp6-/-
mutants. Moreover, the data suggest that LRP4 and LRP6 also influence the
proliferation of human retinal pigment epithelial (hTERT RPE-1) cells in cell culture,
adding to their roles in embryonic development. Furthermore, the study revealed that
LRP4 modulates LRP6-dependent WNT signaling in a more general context, as
demonstrated in hTERT RPE-1 cells.
Overall, these results highlight the important and complex role of LRP4 and LRP6 in
forebrain development and WNT signaling regulation. The findings suggest that LRP4
2
acts as a negative regulator of LRP6-mediated canonical WNT signaling and plays a
critical role in the regulation of mitotic activity of neuronal precursors in the early
developing forebrain. Additionally, the results suggest that LRP5 or an as-yet
undetermined receptor can compensate for the loss of LRP6 as an FZD co-receptor
in the absence of LRP4. These findings provide new insights into the molecular
mechanisms that regulate forebrain development and may have implications for the
understanding and treatment of developmental disorders.
en
dc.format.extent
99 Seiten
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject
early forebrain development
en
dc.subject
WNT signaling pathway
en
dc.subject.ddc
500 Natural sciences and mathematics::500 Natural sciences::500 Natural sciences and mathematics
dc.title
Balancing WNT signaling in early forebrain development
dc.contributor.gender
female
dc.contributor.firstReferee
Hammes-Lewin, Annette
dc.contributor.furtherReferee
Koch, Ursula
dc.date.accepted
2023-08-30
dc.identifier.urn
urn:nbn:de:kobv:188-refubium-40936-7
refubium.affiliation
Biologie, Chemie, Pharmazie
dcterms.accessRights.dnb
free
dcterms.accessRights.openaire
open access