Genetic and Mechanical Disruption of Coordinated Cellular Processes Leads to Congenital Tongue Malformations

Core Concepts

Proper coordination of cell-cell interactions, migration, and differentiation processes in cranial neural crest cells and mesoderm-derived cells is essential for normal tongue development. Genetic or mechanical disruption of these coordinated cellular processes can lead to a range of congenital tongue anomalies.

Abstract

The content examines the role of coordinated cellular processes in normal tongue development and how disruption of these processes can lead to congenital tongue malformations.
Key highlights:

Mice with conditional deletion of the ciliary protein Ofd1 in cranial neural crest cells (CNCC) exhibit a range of tongue anomalies, including aglossia, clefts, hamartomas, and ankyloglossia.
In Ofd1 mutant mice, ectopic brown adipose tissue forms in the tongue due to a lack of proper interaction between CNCC and mesoderm-derived cells. This is caused by downregulation of Hedgehog (Hh) signaling in CNCC.
Ectopic bone formation in the tongue is also observed in Ofd1 mutant mice, arising from abnormal differentiation and migration of CNCC.
Disruption of cell migration patterns required for tongue frenum formation leads to ankyloglossia in Ofd1 mutant mice.
Similar tongue anomalies can be reproduced in wild-type mice by mechanical manipulation of CNCC, demonstrating the importance of coordinated cellular processes for normal tongue development.
Tongue anomalies observed in an OFD1 syndrome patient with a missense mutation recapitulate the findings from the mouse model.
The content highlights how genetic or mechanical disruption of the coordinated cellular processes of cell-cell interaction, migration, and differentiation in CNCC and mesoderm-derived cells can lead to a spectrum of congenital tongue malformations.

Stats

"Ofd1fl;Wnt1Cre(HM) mice have aglossia."
"Ofd1fl/WT;Wnt1Cre(HET) mice have an obvious abnormal-shaped tongue, characterized by the presence of clefts and multiple protrusions."
"The size and location of ectopic bone and sparse tissue varied widely in Ofd1fl/WT;Wnt1Cre(HET) mice."
"Ectopic brown adipose tissue was formed from mesoderm-derived cells, when Ofd1 was deleted from CNCC."
"Myf5 expression was observed in the hypoglossal cord region of wild-type mice at E10, which could not be detected when Ofd1 was deleted from all CNCC."
"Ptch1-negative and -positive domains were overlapped with GFP-negative and -positive domains in Ofd1fl/WT;Wnt1Cre(HET);HprtGFP mice, respectively."
"Ectopic brown adipose tissue was also observed in Smofl/fl;Osr2Cre mice."
"Ectopic bone was observed in the tongue of Ofd1fl;Osr2Cre(HM) mice."

Quotes

"Multiple tongue deformities including cleft, hamartoma and ankyloglossia are also seen in ciliopathies, which yield difficulties in fundamental functions such as mastication and vocalization."
"Perturbations in the function of primary cilia result in a wide spectrum of human diseases: the ciliopathies."
"Congenital tongue anomalies are also observed as non-familial condition in human."
"Tongue development require proper multiple cellular processes (cell-cell contact, migration and differentiation)."

Key Insights Distilled From

Coordinated multiple cellular processes in tongue development

by Kawasaki,M.,... at www.biorxiv.org 01-18-2023

https://www.biorxiv.org/content/10.1101/2023.01.16.524234v1

Deeper Inquiries

How might the insights from this study on coordinated cellular processes in tongue development be applied to develop treatments for congenital tongue anomalies in ciliopathies and non-familial conditions

The insights from this study on coordinated cellular processes in tongue development offer promising avenues for developing treatments for congenital tongue anomalies in ciliopathies and non-familial conditions. Understanding the critical role of primary cilia in regulating signaling pathways and cellular interactions during tongue development provides a foundation for targeted interventions. For ciliopathy-related tongue anomalies, therapies aimed at restoring proper ciliary function or enhancing signaling pathways disrupted by ciliary dysfunction could be explored. This may involve gene therapy to correct ciliary protein mutations or pharmacological approaches to modulate signaling cascades affected by ciliary defects. Additionally, promoting proper cell-cell interactions and migration processes, as highlighted in the study, could be a focus for treatment strategies. For non-familial tongue anomalies, the findings suggest that interventions targeting the cellular processes disrupted by mechanical manipulations could be beneficial. This could involve surgical techniques to correct aberrant cell migration or differentiation, or regenerative medicine approaches to promote normal tissue development in the tongue.

What other developmental processes or organ systems might be affected by disruptions in the coordinated cellular processes described in this study, and how could that inform our understanding of related congenital disorders

Disruptions in the coordinated cellular processes described in this study are likely to impact various developmental processes and organ systems beyond tongue development. The intricate interplay between cranial neural crest-derived cells (CNCC) and mesoderm-derived cells, as well as the crucial role of signaling pathways like Hedgehog (Hh) signaling, are fundamental to organogenesis. Similar disruptions in these processes could lead to congenital disorders affecting other craniofacial structures, such as the palate, teeth, and salivary glands. Moreover, since primary cilia and signaling pathways like Hh signaling are involved in a wide range of developmental processes, disruptions could also affect organ systems outside the craniofacial region. For instance, defects in these cellular processes could contribute to anomalies in the central nervous system, limbs, and internal organs. By understanding the broader implications of these disruptions, we can gain insights into related congenital disorders and potentially uncover novel therapeutic targets for a range of conditions.

Could the mechanical manipulation techniques used in this study to reproduce tongue anomalies in wild-type mice provide a useful model system for further investigating the underlying cellular and molecular mechanisms driving these malformations

The mechanical manipulation techniques used in this study to reproduce tongue anomalies in wild-type mice could indeed serve as a valuable model system for further investigating the underlying cellular and molecular mechanisms driving these malformations. By inducing specific disruptions in cell-cell interactions, migration patterns, and differentiation processes, researchers can dissect the precise contributions of these factors to tongue development and malformations. This model system allows for controlled experiments to study the effects of these disruptions on tongue morphology and function. Additionally, it provides a platform for testing potential therapeutic interventions aimed at restoring normal cellular processes and correcting malformations. By utilizing this model system, researchers can uncover key molecular pathways, identify critical cellular interactions, and potentially develop targeted treatments for congenital tongue anomalies and related conditions.