Altered cerebellar development in mice lacking pituitary adenylate cyclase-activating polypeptide
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Published on: February 21, 2016
Aurélie Allais1, Delphine Burel, Emma R Isaac
1European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, University of Rouen, 76821 Mont-Saint-Aignan, France.
Insights
Pituitary adenylate cyclase-activating polypeptide (PACAP) is crucial for cerebellar development. PACAP-knockout mice showed delayed neuronal differentiation and increased cell death, highlighting PACAP's role in cerebellar ontogenesis.
Area of Science:
- Neuroscience
- Developmental Biology
Background:
- Pituitary adenylate cyclase-activating polypeptide (PACAP) has demonstrated trophic effects during neurodevelopment.
- PACAP and its receptors are present in the cerebellum during critical developmental periods, suggesting a key role in cerebellar ontogenesis.
Purpose of the Study:
- To investigate the role of PACAP in cerebellar cortex development.
- To compare the histogenesis of cerebellar cortex in wild-type and PACAP-knockout (PACAP-/-) mice.
Main Methods:
- Morphometric analysis of cerebellar cortex.
- Quantification of nestin and synaptophysin expression using real-time PCR and Western blot.
- Immunohistochemistry and caspase-3 activation assays.
Main Results:
- PACAP-/- mice exhibited reduced external and internal granule cell layer thickness.
- Synaptophysin expression was significantly decreased in PACAP-/- mice, indicating delayed neuronal differentiation.
- Increased caspase-3 activation was observed in PACAP-/- mice, suggesting elevated cell death.
Conclusions:
- Disruption of the PACAP gene leads to significant alterations in immature cerebellum development.
- PACAP plays a physiological role in cerebellar development by regulating neuronal differentiation and cell death.
Abstract:
Previous studies have demonstrated that pituitary adenylate cyclase-activating polypeptide (PACAP) exerts trophic effects during neurodevelopment. In particular, the occurrence of PACAP and its receptors in the cerebellum during pre- and postnatal periods suggests that it could play a crucial role in ontogenesis of this structure. To test this hypothesis, we compared the histogenesis of cerebellar cortex in wild-type and PACAP-knockout (PACAP-/-) mice at postnatal days (P)4 and 7. Morphometric analysis of PACAP-/- mice revealed a significant reduction in the thickness of the external granule cell layer at P4 and of the internal granule cell layer at P7. Expression of nestin, a neural precursor marker, and synaptophysin, a mature neuronal marker, was quantified by real-time PCR and Western blot. No modification of nestin expression was noticed between wild-type and PACAP-/- mice, but a substantial decrease in synaptophysin expression was observed in PACAP-/- mice at P4 and P7. Immunohistochemistry revealed a reduction in synaptophysin labelling in the molecular and internal granule cell layers of PACAP-/- mice at P7. Caspase-3 activation was significantly increased in PACAP-/- mice at P4 and P7. Autoradiographic studies revealed no difference in PACAP binding site distributions and PACAP was effective at stimulating cAMP production in both wild-type and PACAP-/- cultured granule cells. This study demonstrates that disruption of the PACAP gene induces alteration of the immature cerebellum. Neuronal differentiation of granule cells was delayed whereas cell death that naturally occurs during ontogeny was increased in PACAP-/- mice. These data provide the first evidence of a physiological role for PACAP during cerebellar development.
