Altered Notch Signaling in Developing Molar Teeth of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)-Deficient Mice

  • B. D. Fulop
  • B. Sandor
  • E. Szentleleky
  • E. Karanyicz
  • D. Reglodi
  • B. Gaszner
  • R. Zakany
  • H. Hashimoto
  • T. Juhasz
  • A. TamasEmail author


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.


PACAP-deficient mice Notch signaling DLL1, 3, 4, Jagged1, 2 Notch1, 2, 3, 4 CSL TACE NUMB Development of molar tooth 



Adenylate cyclase


Arbitrary unit


Bone morphogenetic protein


Cyclic adenosine monophosphate


CBF1 humans/Su (H) Drosophila/LAG1 Caenorhabditis elegans transcription factor


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


Extracellular signal-regulated kinases


Embryonic day


Fibroblast growth factor


Fibroblast growth factor receptor


Glioma-associated oncogene


Gq protein


Gs protein


Hairy and enhancer of split gene family


Hairy/enhancer-of-split related with YRPW motif protein gene family


Heterozygous PACAP-deficient mice


c-Jun N-terminal kinase


Homozygous PACAP-deficient mice


Lunatic fringe


Notch intracellular domain


NUMB, endocytic adaptor protein


p38 mitogen-activated protein kinases


PACAP type I receptor


Pituitary adenylate cyclase-activating polypeptide


Phosphate-buffered saline with Tween-20




Protein kinase A


Postnatal day


Protein patched homolog 1 protein (SHH receptor)


Runt-related transcription factor 2


Sonic hedgehog


TNF-α converting enzyme (ADAM 17 endopeptidase)


Vasoactive intestinal peptide

VPAC1, 2

Vasoactive intestinal peptide receptors 1, 2


Wingless-related integration site


Wild type


Funding information

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • B. D. Fulop
    • 1
  • B. Sandor
    • 1
    • 2
  • E. Szentleleky
    • 3
  • E. Karanyicz
    • 3
  • D. Reglodi
    • 1
  • B. Gaszner
    • 1
  • R. Zakany
    • 3
  • H. Hashimoto
    • 4
    • 5
    • 6
    • 7
    • 8
    • 9
    • 10
  • T. Juhasz
    • 3
  • A. Tamas
    • 1
    Email author
  1. 1.Department of Anatomy, MTA-PTE PACAP Research Team, Centre for NeuroscienceUniversity of Pecs Medical SchoolPecsHungary
  2. 2.Department of Dentistry, Oral and Maxillofacial SurgeryUniversity of Pecs Medical SchoolPecsHungary
  3. 3.Department of Anatomy, Histology and Embryology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  4. 4.Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical SciencesOsaka UniversitySuitaJapan
  5. 5.Molecular Research Center for Children’s Mental Development, United Graduate School of Child DevelopmentOsaka UniversityOsakaJapan
  6. 6.Molecular Research Center for Children’s Mental Development, United Graduate School of Child DevelopmentKanazawa UniversityKanazawaJapan
  7. 7.Molecular Research Center for Children’s Mental Development, United Graduate School of Child DevelopmentHamamatsu University School of MedicineShizuokaJapan
  8. 8.Molecular Research Center for Children’s Mental Development, United Graduate School of Child DevelopmentChiba UniversityChibaJapan
  9. 9.Molecular Research Center for Children’s Mental Development, United Graduate School of Child DevelopmentUniversity of FukuiFukuiJapan
  10. 10.Division of Bioscience, Institute for Datability ScienceOsaka UniversitySuitaJapan

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