Wnt3 is a protein that serves as a signaling molecule, acting like a messenger carrying specific instructions between cells. It belongs to the Wnt family of proteins, all of which are secreted by cells to influence the behavior of neighboring cells. These Wnt proteins play a role in orchestrating various cellular processes by transmitting information across cell membranes.
The Wnt Signaling Pathway
The Wnt3 protein delivers its message primarily through the canonical Wnt signaling pathway. This process begins when Wnt3, a secreted ligand, binds to specific receptor proteins on the surface of a target cell. These receptors are a combination of a Frizzled (Fz) family receptor and a co-receptor from the LRP5/6 family.
This interaction leads to the inactivation of a protein complex known as the “destruction complex,” which normally keeps levels of a protein called β-catenin low. The destruction complex includes proteins such as glycogen synthase kinase 3 beta (GSK3β), adenomatous polyposis coli (APC), and Axin. Once inhibited, β-catenin is no longer targeted for degradation.
As a result, β-catenin accumulates in the cell’s cytoplasm and moves into the nucleus. Inside the nucleus, β-catenin partners with transcription factors belonging to the TCF/LEF family. This partnership activates the transcription of specific genes, triggering changes in cell behavior and function.
Role in Embryonic Development
Wnt3 signaling plays a role in the orchestration of embryonic development, particularly in shaping the body plan. It establishes the anterior-posterior, or head-to-tail, axis of the developing embryo. This includes its participation in gastrulation, where the primitive streak forms and the three primary germ layers, including the mesoderm, are established.
The protein also contributes to the formation and patterning of the central nervous system (CNS). Wnt3 is involved in neural induction, the initial step where neural tissue is specified from the ectoderm, and subsequently in the formation of the neural tube, which develops into the brain and spinal cord. Its influence extends to guiding axons, the long projections of nerve cells, and facilitating the development of synapses, the connections between neurons.
Wnt3 is also important for the proper formation of limbs. It is required for the establishment and maintenance of the apical ectodermal ridge (AER), a specialized structure in the limb bud. The AER produces growth factors, such as FGFs, which are necessary for the limb to grow outward from the body axis in a proximo-distal direction, ensuring limbs develop with the correct structure and orientation.
Function in Adult Tissues
After embryonic development, Wnt3 continues to perform important functions, primarily in the maintenance and repair of adult tissues. It plays a role in managing adult stem cell populations, which are responsible for replenishing cells in tissues that undergo constant renewal.
In the lining of the intestines, for example, Wnt3 contributes to the activity of intestinal stem cells (ISCs) located in structures called crypts. Paneth cells, specialized cells within the intestinal crypts, secrete Wnt3 and other Wnt factors, providing a localized signal that helps maintain the ISCs. This sustained signaling prompts these stem cells to divide and produce new cells, ensuring the continuous renewal of the intestinal lining.
Similarly, Wnt3 signaling influences stem cells in the skin. It helps regulate epidermal stem cells and hair follicle stem cells, guiding their division and differentiation to replace old skin cells and support hair growth. Wnt3 thereby contributes to the ongoing repair and regeneration processes that keep adult tissues healthy and functional.
Dysregulation in Disease
When the Wnt3 signaling pathway does not function correctly, it can lead to various disease states, most notably cancer. If the pathway becomes abnormally active, it can cause cells to grow and divide without control. This uncontrolled proliferation is a defining characteristic of tumor formation.
Colorectal cancer (CRC) provides a clear example of Wnt3 pathway dysregulation. In many cases of CRC, mutations in genes such as APC or β-catenin lead to the continuous activation of the canonical Wnt pathway. The elevated expression of Wnt3 itself is often observed in colorectal cancer tissues, contributing to tumor progression.
Beyond colorectal cancer, Wnt3 dysregulation has been observed in other malignancies, including gastric, lung, and breast cancers, where it also contributes to increased cell proliferation and tumor development. Wnt3a, a closely related Wnt protein, has been implicated in the development of fibrosis in organs such as the lungs and kidneys. In these conditions, Wnt3a can promote the differentiation of cells into myofibroblasts, leading to excessive tissue scarring.