Impact of Motile Ciliopathies on Human Development and Clinical Consequences in the Newborn

Abstract

Motile cilia are hairlike organelles that project outward from a tissue-restricted subset of cells to direct fluid flow. During human development motile cilia guide determination of the left-right axis in the embryo, and in the fetal and neonatal periods they have essential roles in airway clearance in the respiratory tract and regulating cerebral spinal fluid flow in the brain. Dysregulation of motile cilia is best understood through the lens of the genetic disorder primary ciliary dyskinesia (PCD). PCD encompasses all genetic motile ciliopathies resulting from over 60 known genetic mutations and has a unique but often underrecognized neonatal presentation. Neonatal respiratory distress is now known to occur in the majority of patients with PCD, laterality defects are common, and very rarely brain ventricle enlargement occurs. The developmental function of motile cilia and the effect and pathophysiology of motile ciliopathies are incompletely understood in humans. In this review, we will examine the current understanding of the role of motile cilia in human development and clinical considerations when assessing the newborn for suspected motile ciliopathies.

Cerebral Malaria Model Applying Human Brain Organoids

“…Caspase-3 is a marker of cell death and plays a crucial role in the development of brain injuries and neurodegenerative diseases, showing an increased profile [ 116 , 117 ]. Additionally, it is described that microcephaly brain organoids showed a significant increase in CASP3+ cells [ 118 ]. Our findings showed that all conditions had positive cells for CASP3 in brain organoids for all conditions, but without a higher concentration.…”

Understanding laterality disorders and the left-right organizer: Insights from zebrafish

“…In some of cases, SIT is a consequence of a broader syndrome called primary ciliary dyskinesia (PCD) (Praveen, Davis, and Katsanis 2015;Wallmeier et al, 2020;Amack, 2022). PCD is commonly caused by mutations that affect dynein arms of motile cilia (Lucas et al, 2020;Horani and Ferkol 2021;Hyland and Brody 2021). PCD patients have paralyzed cilia that cannot move mucus to clear airways (called mucociliary clearance), which leads to a buildup of mucus in craniofacial sinuses and in pulmonary airways that and ultimately affects lung function and cause bronchiectasis (Storm van's Gravesande and Omran 2005;Leigh et al, 2019).…”

Structures and functions of cilia during vertebrate embryo development

“…In vertebrate embryos, transcriptionally regulated variations in ciliary architecture and composition give rise to distinct types of cilia in different types of cells (Gerdes et al, 2009 ; Hyland & Brody, 2021 ; Mitchison & Valente, 2017 ). Most cells assemble an immotile cilium—referred to as a “primary cilium” because there is one cilium per cell—that contains membrane proteins that can sense external chemical and/or mechanical cues, and thereby serves as a signaling hub for the cell.…”

“…Motile cilia are typically found on specialized epithelial multiciliated cells (MCCs) that project ~50–300 cilia from their apical surface that beat in sync to move fluids in one direction (Brooks & Wallingford, 2014 ) (Figure 2b ). In human embryos, MCCs develop in the respiratory tracts, brain ventricles, and reproductive tracts (Hoque et al, 2022 ; Hyland & Brody, 2021 ; Ringers et al, 2020 ). MCCs in the respiratory tract move mucus to remove trapped dirt and pathogens (called mucociliary clearance) to protect against infections.…”

“…Work over the last two decades in the fields of genetics, cell and molecular biology, and embryology have linked defects in the formation and/or function of cilia with several congenital multisystem disorders that are referred to as ciliopathies. Ciliopathies present with a broad spectrum of severity, partially overlapping phenotypes, and genetic heterogeneity (Focșa et al, 2021 ; Hildebrandt et al, 2011 ; Horani & Ferkol, 2021 ; Hyland & Brody, 2021 ; Waters & Beales, 2011 ). While several gene mutations that alter cilia are embryonic lethal, a window into the wide‐ranging functions for cilia during vertebrate embryonic development is provided by the breadth of multisystem birth defects associated with ciliopathies.…”