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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. Tamas
Article

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.

Keywords

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

Abbreviations

AC

Adenylate cyclase

AU

Arbitrary unit

BMP

Bone morphogenetic protein

cAMP

Cyclic adenosine monophosphate

CSL

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

Notes

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

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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
  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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