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. Tamás

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournalJournal of Molecular Neuroscience
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Pituitary Adenylate Cyclase-Activating Polypeptide
Tooth
Ameloblasts
Odontoblasts
Hedgehogs
Notch2 Receptor
Up-Regulation
Notch Receptors
Ligands
Ectoderm
Neural Crest
Caenorhabditis elegans
Neuroprotective Agents
Dentin
Dental Enamel
Neuropeptides
Nervous System
Drosophila
Transcription Factors
Genotype

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Altered Notch Signaling in Developing Molar Teeth of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)-Deficient Mice. / Fulop, B. D.; Sandor, B.; Szentleleky, E.; Karanyicz, E.; Reglodi, D.; Gaszner, B.; Zakany, R.; Hashimoto, H.; Juhasz, T.; Tamás, A.

In: Journal of Molecular Neuroscience, 01.01.2018.

Research output: Contribution to journalArticle

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AU - Sandor, B.

AU - Szentleleky, E.

AU - Karanyicz, E.

AU - Reglodi, D.

AU - Gaszner, B.

AU - Zakany, R.

AU - Hashimoto, H.

AU - Juhasz, T.

AU - Tamás, A.

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AB - 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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