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

Abstract

Vital internal organs display a left-right (LR) asymmetric arrangement that is established during embryonic development. Disruption of this LR asymmetry—or laterality—can result in congenital organ malformations. Situs inversus totalis (SIT) is a complete concordant reversal of internal organs that results in a low occurrence of clinical consequences. Situs ambiguous, which gives rise to Heterotaxy syndrome (HTX), is characterized by discordant development and arrangement of organs that is associated with a wide range of birth defects. The leading cause of health problems in HTX patients is a congenital heart malformation. Mutations identified in patients with laterality disorders implicate motile cilia in establishing LR asymmetry. However, the cellular and molecular mechanisms underlying SIT and HTX are not fully understood. In several vertebrates, including mouse, frog and zebrafish, motile cilia located in a “left-right organizer” (LRO) trigger conserved signaling pathways that guide asymmetric organ development. Perturbation of LRO formation and/or function in animal models recapitulates organ malformations observed in SIT and HTX patients. This provides an opportunity to use these models to investigate the embryological origins of laterality disorders. The zebrafish embryo has emerged as an important model for investigating the earliest steps of LRO development. Here, we discuss clinical characteristics of human laterality disorders, and highlight experimental results from zebrafish that provide insights into LRO biology and advance our understanding of human laterality disorders.

Cdonis required for organ Left-Right patterning via regulating DFCs migration and the sequential ciliogenesis

“…In zebrafish, the transgenic line Tg(sox17:EGFP) has been developed to label the DFC/KV cells (Liu et al, 2019), and several developmental steps have been identified to build a functional KV/Cilia. DFCs appear at mid-epiboly stages, migrate, proliferate, and then undergo a mesenchymal-to-epithelial transition to form KV in early somite stage (Forrest et al, 2022). KV develops directional fluid flow and establishes LR signaling, and then breaks down around 18 hpf when KV cells undergo a epithelial to mesenchymal transition (Amack, 2021) and migrate away to incorporate into muscle and notochord (Ikeda et al, 2022).…”

“…Establishment of left-right patterning (LR Patterning) is an important event in early embryonic development, organ asymmetry defect is closely related to the occurrence of various congenital diseases such as congenital heart disease and schizophrenia (Gabriel and Lo, 2020; Huang et al, 2014). Although the mechanisms of establishment of organ LR patterning are complex and diverse in different animal models (Hamada and Tam, 2020; Onuma et al, 2020; Zhu et al, 2020), the role of Kupffer’s vesicle (KV)/Node-Cilia axis in zebrafish and mice is extremely conservative (Forrest et al, 2022; Grimes and Burdine, 2017; Little and Norris, 2021). In zebrafish, the normal development of KV precursor cells (Named dorsal forerunner cells (DFCs) and KV morphogenesis/Ciliogenesis play crucial roles in initiating left-sided signals in the embryonic lateral plate mesoderm (LPM) (Grimes and Burdine, 2017).…”

Prevalence of tooth agenesis and supernumerary teeth related to different Thai cleft lip and cleft palate populations

“…The system was classi ed into two categories: the presence of a tooth (0) and the absence of speci c tooth types, each assigned a distinct value. Central incisor (1), lateral incisor (2), canine (4), rst premolar (8), second premolar (16), rst molar (32), second molar (64), and third molar (128) were each associated with their respective values. The cumulative score was derived from the sum of these values corresponding to the missing tooth types in each quadrant, yielding a unique numeric representation for each pattern of tooth agenesis.…”

“…It has been suggested that some molecules, acting as the left-right organizers, controlling laterality, may be both involved during palatogenesis and odontogenesis (32). Some genes involved in left-right patterning contribute to facial asymmetry of the CLP spectrum (33).…”

New insights on the genetics of hair whorls from twins and the Southern hemisphere

“…Their developmental origins and the mechanisms determining their rotation direction are unclear. Both genetics and physical constraints could be implicated in determining the location and orientation of whorls, as in other lateralisation phenomena (Forrest et al 2022). As is Blaschko lines, which include whorl-like distributions on the scalp surface (Happle 2013), hair whorls may be related with cell migration processes but there is no current experimental evidence for this hypothesis.…”