Unit:
Department of BiologyLibrary of the School of Science
Author:
Kokkorakis Nikolaos
Dissertation committee:
Παπαζαφείρη Παναγιώτα (Επιβλέπουσα), Αναπληρώτρια Καθηγήτρια, Τμήμα Βιολογίας, ΕΚΠΑ
Μάτσα Ρεβέκκα, Συνεργαζόμενη Ερευνήτρια, Ελληνικό Ινστιτούτο Παστέρ
Γαϊτάνου Μαρία, Κύρια Ερευνήτρια, Ελληνικό Ινστιτούτο Παστέρ
Εμμανουηλίδου Ευαγγελία, Επίκουρη Καθηγήτρια, Τμήμα Χημείας, ΕΚΠΑ
Ευθυμιόπουλος Σπυρίδων, Καθηγητής, Τμήμα Βιολογίας, ΕΚΠΑ
Θωμαΐδου Δήμητρα, Διευθύντρια Ερευνών, Ελληνικό Ινστιτούτο Παστέρ
Στραβοπόδης Δημήτριος, Αναπληρωτής Καθηγητής, Τμήμα Βιολογίας, ΕΚΠΑ
Original Title:
Μελέτη του ρόλου της ομάδας των Minibrain/DYRK κινασών στην ανάπτυξη του νευρικού συστήματος
Translated title:
Study of the role of Minibrain/DYRK kinases group in the development of the nervous system
Summary:
Cross-talk between Mirk/Dyrk1B kinase and Sonic hedgehog (Shh)/Gli signaling pathway affects physiology and pathology. The observations of the present doctoral thesis reveal a novel role for Dyrk1B in regulating ventral progenitor and neuron subtypes in the embryonic chick spinal cord (SC) via the Shh pathway. Initially, it was investigated the developmental pattern of Dyrk1B expression in mouse and chick CNS during embryogenesis, postnatal, and adult life. It was shown that Dyrk1B is expressed by proliferating neuroblasts and postmitotic neurons of the brain and spinal cord as well as its expression in the dentate gyrus of the mouse brain marks all stages of secondary and adult neurogenesis. Furthermore, Dyrk1B expression is decreased during mouse and chick CNS development, indicating an important role of Dyrk1B in the first stages of neurogenesis. In ovo gain-and-loss-of-function approaches at E2 showed that Dyrk1B affects the proliferation and differentiation of neuronal progenitors at E4 and impacts apoptosis specifically in the motor neuron (MN) domain. Especially, Dyrk1B overexpression decreases the numbers of ventral progenitors, MNs, and V2a interneurons, while the pharmacological inhibition of endogenous Dyrk1B kinase activity by AZ191 inhibitor administration increases the numbers of ventral progenitors and MNs. Mechanistically, Dyrk1B overexpression suppresses Shh, Gli2, and Gli3 mRNA levels, while conversely, Shh, Gli2, and Gli3 transcription is increased in the presence of Dyrk1B inhibitor AZ191 or Smoothened agonist SAG. Most importantly, in phenotype rescue experiments, SAG restores the Dyrk1B-mediated dysregulation of ventral progenitors. In addition, at E6, Dyrk1B selectively affects the medial lateral motor column (LMCm), consistent with the expression of Shh in this region. Collectively, these observations reveal a novel regulatory function of Dyrk1B kinase in suppressing the Shh/Gli pathway and thus affecting ventral progenitors in the developing spinal cord. These results make Dyrk1B kinase a possible therapeutic target for motor neuron diseases.
Main subject category:
Science
Keywords:
Neural tube, Ventral progenitors, Motor neurons, Dyrk1B kinase, Shh signaling
Number of references:
276
