Integrative Analysis of Key Signalling Pathways in Neural Tube Defects: From Molecular Mechanisms to Therapeutic Strategies

Abstract

Neural tube defects (NTDs), such as anencephaly and spina bifida, are prevalent congenital anomalies of the central nervous system. These defects can give rise to severe lifelong disabilities and incur substantial healthcare expenses for the affected individuals. The occurrence of NTDs is caused by multiple factors, including molecular regulatory mechanisms and environmental factors. This article comprehensively reviews the underlying mechanisms of three crucial signalling pathways associated with neural tube development: the Wnt/Planar Cell Polarity (PCP) signalling pathway, the Sonic Hedgehog signalling pathway and the Notch signalling pathway, and, on this basis, delves into the potential molecular therapeutic strategies for NTDs. This review is of great significance for comprehensively elucidating the molecular causes of NTDs and expanding prevention and treatment strategies for related congenital anomalies.

Keywords: NTDS; Notch signalling pathway; Sonic Hedgehog signalling pathway; Wnt/PCP signalling pathway; anencephaly; spina bifida.

FIGURE 1

Wnt/PCP, Sonic Hedgehog and Notch signalling pathways regulate neural tube development. (a) FZD, ANKRD6, CELSR, DVL, VANGL and PRICKLE are core proteins of the Wnt/PCP signalling pathway. When Wnt signalling proteins bind to FZD receptors, downstream proteins such as DVL, ANKRD6, DAAM, Rho and Rock are sequentially activated. Among them, DAAM negatively regulates the activity of DVL, thereby modulating the pathway. SCRIB1 and CELSR regulate the activity of VANGL, which in turn affects the PRICKLE protein. PRICKLE inhibits the activity of DVL, maintaining the activity of the Wnt/PCP pathway within the normal range and promoting the convergence of both sides of the neural plate to form neural folds. (b) When the Notch receptor binds to the Notch ligand, TACE catalyses the extracellular region to form NECD, and γ‐secretase catalyses the intracellular region to form NICD. Subsequently, NICD combines with CSL molecules to activate the expression of Notch‐related genes, promoting the formation and fusion of neural folds to develop the neural tube. (c) Ptch and Smo are crucial transport receptors in the Shh signalling pathway. Upon activation by Shh signalling proteins, Ptch is translocated from the intracellular to the extracellular space through Ptch protein channels, whereas Smo moves intracellularly through Smo protein channels to inhibit the activity of GPR161 and release the inhibitory state of PKA. PKA promotes the dissociation of the Sufu‐Gli complex. Dephosphorylation of Gli activates the transcription of Shh‐related genes, facilitating the fusion of neural folds to form the neural tube.