Roles of Wnt7a in embryo development, tissue homeostasis, and human diseases

Abstract

Human Wnt family comprises 19 proteins which are critical to embryo development and tissue homeostasis. Binding to different frizzled (FZD) receptor, Wnt7a initiates both β‐catenin dependent pathway, and β‐catenin independent pathways such as PI3K/Akt, RAC/JNK, and extracellular signal‐regulated kinase 5/peroxisome proliferator‐activated receptor‐γ. In the embryo, Wnt7a plays a crucial role in cerebral cortex development, synapse formation, and central nervous system vasculature formation and maintenance. Wnt7a is also involved in the development of limb and female reproductive system. Wnt7a mutation leads to human limb malformations and animal female reproductive system defects. Wnt7a is implicated in homeostasis maintenance of skeletal muscle, cartilage, cornea and hair follicle, and Wnt7a treatment may be potentially applied in skeletal muscle dystrophy, corneal damage, wound repair, and hair follicle regeneration. Wnt7a plays dual roles in human tumors. Wnt7a is downregulated in lung cancers, functioning as a tumor suppressor, however, it is upregulated in several other malignancies such as ovarian cancer, breast cancer, and glioma, acting as a tumor promoter. Moreover, Wnt7a overexpression is associated with inflammation and fibrosis, but its roles need to be further investigated.

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

“…Moreover, it also contributes to anteroposterior patterning by maintaining sonic hedgehog expression (32)(33)(34). Consistently, mutations in WNT7A cause limb malformations in Al-Awadi-Raas-Rothschild syndrome (AARRS) and Fuhrmann syndrome (FS) (31)(32)(33)(34)(35)(36)(37). Patients with AARRS display short upper limbs, severe malformations of the lower limbs, hypoplastic pelvis, anteriorly displaced genitalia, underdeveloped nails, and absence of uterus.…”

“…It is expressed in the dorsal ectoderm and involved in the formation of the dorsoventral axis in limb development (32)(33)(34). Moreover, it also contributes to anteroposterior patterning by maintaining sonic hedgehog expression (32)(33)(34). Consistently, mutations in WNT7A cause limb malformations in Al-Awadi-Raas-Rothschild syndrome (AARRS) and Fuhrmann syndrome (FS) (31)(32)(33)(34)(35)(36)(37).…”

“…WNT7A forms a receptor complex with LRP6 and FZD5 in order to activate the canonical WNT signaling pathway (31,32). It is expressed in the dorsal ectoderm and involved in the formation of the dorsoventral axis in limb development (32)(33)(34). Moreover, it also contributes to anteroposterior patterning by maintaining sonic hedgehog expression (32)(33)(34).…”

“…Patients with AARRS display short upper limbs, severe malformations of the lower limbs, hypoplastic pelvis, anteriorly displaced genitalia, underdeveloped nails, and absence of uterus. The phenotype observed in FS is milder (e.g., solely ulnar deficiency and oligodactyly) since this is due to only a reduced function of the protein compared to complete loss-offunction mutations as seen in AARRS (32,(34)(35)(36)(37). Although both are rare autosomal recessive disorders, different mutations contribute to the highly variable disease phenotypes (31, 34-36, 38, 39).…”

Bioinformatics Analysis Revealed Novel 3′UTR Variants Associated with Intellectual Disability

“…WNT7A is involved in dendritic growth, since its signaling is critical to dendritic spine growth and synaptic strength regulation [29], synapse density and amount mediation [30], etc. Meanwhile, it also has a significant impact on macrophage responses by inducing a unique phenotype of monocyte-derived macrophages [55], and is related to embryo development and tissue homeostasis as it can initiate both β-catenin dependent and independent pathways [56]. The basal ganglia, part of the subcortical structures of the brain, is involved in memory, emotion, pleasure, and hormone production.…”