TY - BOOK

T1 - Molecular mechanisms balancing the output of ciliary TGFB/BMP signaling

AU - Leischner Fialová, Jindriska

PY - 2024

Y1 - 2024

N2 - TGFB/BMP signaling is a crucial pathway governing various cellular processes during embryonic and fetal development. Understanding the coordination of this signaling pathway in different tissues and organs and during their development is essential for comprehending pathophysiological manifestation of their dysfunction. Primary cilia, solitary organelles exposed on the surface of cells, have emerged as pivotal signaling hubs for mediating various signaling pathways, including TGFB/BMP. This thesis seeks to deepen our knowledge on how primary cilia regulate TGFB/BMP signaling, with a particular focus on their involvement in brain and heart development.Starting with the introduction into current knowledge about primary cilia and their role in coordination of signaling and embryonic and fetal development, this thesis presents three manuscripts in preparation for publication.Manuscript I comprises a comprehensive literature review underscoring the significance of primary cilia in the etiology of primary microcephaly, emphasizing their role in expanding the pool of radial glial cells and other processes governing size and function of the neocortex. Additionally, we compiled a list of candidate proteins suitable for cilia investigation in the context of microcephaly. This manuscript also delves into the potential functional role of primary cilia in mediating neural regeneration. To elucidate the mechanisms through which primary cilia contribute to primary microcephaly, in Manuscript II we investigate the function of the MCPH protein, RRP7A, in orchestrating TGFΒ/BMP signaling at the primary cilium. Our findings provide evidence that mutation in RRP7A disrupts canonical TGFB/BMP signaling. Analysis of the RRP7A interactome reveals that the mutation affects clathrin-dependent endocytosis events at the ciliary base, crucial for proper activation of the canonical TGFΒ/BMP pathway. This disruption leads to ciliary resorption defects, ultimately resulting in a reduced expansion of apical radial glial cells crucial for corticogenesis. Shifting the focus to heart development, Manuscript III focuses on investigation of TAK1 in non-canonical TGFΒ/BMP signaling associated with congenital heart disease. The study reveals the ciliary coordination of TAK1 and its upstream effectors during cardiomyogenesis, which when disrupted, leads to downregulation of key cardiac transcription factors, sarcomeric proteins and ECM components, ultimately resulting in cardiac defects such as dilated atrium, trabeculation defects, and tachycardia accompanied by extracardiac anomalies.This thesis introduces novel insights into the diverse functionalities of primary cilia, underscoring their pivotal role in coordinating intricate signaling pathways crucial for embryonic and fetal development.

AB - TGFB/BMP signaling is a crucial pathway governing various cellular processes during embryonic and fetal development. Understanding the coordination of this signaling pathway in different tissues and organs and during their development is essential for comprehending pathophysiological manifestation of their dysfunction. Primary cilia, solitary organelles exposed on the surface of cells, have emerged as pivotal signaling hubs for mediating various signaling pathways, including TGFB/BMP. This thesis seeks to deepen our knowledge on how primary cilia regulate TGFB/BMP signaling, with a particular focus on their involvement in brain and heart development.Starting with the introduction into current knowledge about primary cilia and their role in coordination of signaling and embryonic and fetal development, this thesis presents three manuscripts in preparation for publication.Manuscript I comprises a comprehensive literature review underscoring the significance of primary cilia in the etiology of primary microcephaly, emphasizing their role in expanding the pool of radial glial cells and other processes governing size and function of the neocortex. Additionally, we compiled a list of candidate proteins suitable for cilia investigation in the context of microcephaly. This manuscript also delves into the potential functional role of primary cilia in mediating neural regeneration. To elucidate the mechanisms through which primary cilia contribute to primary microcephaly, in Manuscript II we investigate the function of the MCPH protein, RRP7A, in orchestrating TGFΒ/BMP signaling at the primary cilium. Our findings provide evidence that mutation in RRP7A disrupts canonical TGFB/BMP signaling. Analysis of the RRP7A interactome reveals that the mutation affects clathrin-dependent endocytosis events at the ciliary base, crucial for proper activation of the canonical TGFΒ/BMP pathway. This disruption leads to ciliary resorption defects, ultimately resulting in a reduced expansion of apical radial glial cells crucial for corticogenesis. Shifting the focus to heart development, Manuscript III focuses on investigation of TAK1 in non-canonical TGFΒ/BMP signaling associated with congenital heart disease. The study reveals the ciliary coordination of TAK1 and its upstream effectors during cardiomyogenesis, which when disrupted, leads to downregulation of key cardiac transcription factors, sarcomeric proteins and ECM components, ultimately resulting in cardiac defects such as dilated atrium, trabeculation defects, and tachycardia accompanied by extracardiac anomalies.This thesis introduces novel insights into the diverse functionalities of primary cilia, underscoring their pivotal role in coordinating intricate signaling pathways crucial for embryonic and fetal development.

M3 - Ph.D. thesis

BT - Molecular mechanisms balancing the output of ciliary TGFB/BMP signaling

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -