Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with neuroprotective and neurotrophic effects. This suggests its influence on the development of teeth, which are, similarly to the nervous system, ectoderm and neural crest derivatives. Our earlier studies have shown morphological differences between wild-type (WT) and PACAP-deficient mice, with upregulated sonic hedgehog (SHH) signaling in the lack of PACAP. Notch signaling is a key element of proper tooth development by regulating apoptosis and cell proliferation. In this study, our main goal was to evaluate the possible effects of PACAP on Notch signaling pathway. Immunohistochemical staining was performed of Notch receptors (Notch1, 2, 3, 4), their ligands [delta-like protein (DLL)1, 3, 4, Jagged1, 2], and intracellular target molecules [CSL (CBF1 humans/Su (H) Drosophila/LAG1 Caenorhabditis elegans transcription factor); TACE (TNF-α converting enzyme), NUMB] in molar teeth of 5-day-old WT, and homozygous and heterozygous PACAP-deficient mice. We measured immunopositivity in the enamel-producing ameloblasts and dentin-producing odontoblasts. Notch2 receptor and DLL1 expression were elevated in ameloblasts of PACAP-deficient mice compared to those in WT ones. The expression of CSL showed similar results both in the ameloblasts and odontoblasts. Jagged1 ligand expression was elevated in the odontoblasts of homozygous PACAP-deficient mice compared to WT mice. Other Notch pathway elements did not show significant differences between the genotype groups. The lack of PACAP leads to upregulation of Notch pathway elements in the odontoblast and ameloblast cells. The underlying molecular mechanisms are yet to be elucidated; however, we propose SHH-dependent and independent processes. We hypothesize that this compensatory upregulation of Notch signaling by the lack of PACAP could represent a salvage pathway in PACAP-deficient animals.
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Abbreviations
- AC:
-
Adenylate cyclase
- AU:
-
Arbitrary unit
- BMP :
-
Bone morphogenetic protein
- cAMP:
-
Cyclic adenosine monophosphate
- CSL:
-
CBF1 humans/Su (H) Drosophila/LAG1 Caenorhabditiselegans transcription factor
- DAPI:
-
4′,6-Diamidino-2-phenylindole (nucleus stain)
- DLL1, 3, and 4:
-
Delta-like proteins 1, 3, and 4 encoded by the DLL1, 3, and 4 genes
- ERK:
-
Extracellular signal-regulated kinases
- E:
-
Embryonic day
- FGF:
-
Fibroblast growth factor
- FGFR:
-
Fibroblast growth factor receptor
- GLI:
-
Glioma-associated oncogene
- Gq :
-
Gq protein
- Gs :
-
Gs protein
- Hes:
-
Hairy and enhancer of split gene family
- Hey:
-
Hairy/enhancer-of-split related with YRPW motif protein gene family
- HZ:
-
Heterozygous PACAP-deficient mice
- JNK:
-
c-Jun N-terminal kinase
- KO:
-
Homozygous PACAP-deficient mice
- LF:
-
Lunatic fringe
- NICD:
-
Notch intracellular domain
- NUMB:
-
NUMB, endocytic adaptor protein
- p38:
-
p38 mitogen-activated protein kinases
- PAC1:
-
PACAP type I receptor
- PACAP:
-
Pituitary adenylate cyclase-activating polypeptide
- PBST:
-
Phosphate-buffered saline with Tween-20
- PI3K:
-
Phosphatidylinositol-3-kinases
- PKA:
-
Protein kinase A
- PN:
-
Postnatal day
- PTCH1:
-
Protein patched homolog 1 protein (SHH receptor)
- RUNX2:
-
Runt-related transcription factor 2
- SHH:
-
Sonic hedgehog
- TACE:
-
TNF-α converting enzyme (ADAM 17 endopeptidase)
- VIP:
-
Vasoactive intestinal peptide
- VPAC1, 2:
-
Vasoactive intestinal peptide receptors 1, 2
- WNT:
-
Wingless-related integration site
- WT:
-
Wild type
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Funding
This study was funded by the Hungarian Scientific Research Fund K119759; GINOP-2.3.2-15-2016-00050 “PEPSYS”; EFOP-3.6.3-VEKOP-16-15 2017-00008; Hungarian Brain Research Program 2017-1.2.1-NKP-2017-00002; EFOP-3.6.2-16-2017-00008 “The role of neuro-inflammation in neurodegeneration: from molecules to clinics”; Hungarian Academy of Sciences MTA-TKI-14016; Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary 20765-3/2018/FEKUTSTRAT; University of Pecs Medical School KA Research Grant 2018/08; EFOP 3.6.1-16.2016.00004; TAMOP-4.2.4.A/2-11-1-2012-0001; New Hungarian National Excellence Program UNKP-16-4-IV; Bolyai Scholarship (Andrea Tamas, Tamas Juhasz); Szodoray Lajos Fundation (Tamas Juhasz); OTKA Bridging Fund (Tamas Juhasz).
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Fulop, B.D., Sandor, B., Szentleleky, E. et al. Altered Notch Signaling in Developing Molar Teeth of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)-Deficient Mice. J Mol Neurosci 68, 377–388 (2019). https://doi.org/10.1007/s12031-018-1146-7
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DOI: https://doi.org/10.1007/s12031-018-1146-7