Ryk, a receptor-like kinase, is a novel Wnt receptor. It is involved in the Wnt-Ca2+ signaling pathway and other Wnt-related signaling. Ryk plays a crucial role in multiple essential biological processes, including embryonic development, cell polarity determination, and axon guidance [1,4,5,6]. Genetic models, especially gene knockout (KO) mouse models, have been valuable in studying its functions.

In Ryk loss-of-function mice, various embryonic abnormalities are observed, such as disruptions in skeletal, craniofacial, and cardiac development [1]. In midgut development, loss of Ryk phenocopies the Wnt5a-/-phenotype, perturbing post-mitotic pathfinding and leading to apoptosis, highlighting its role in midgut elongation [2]. In the lung, Ryk mutant mice exhibit lung hypoplasia, inflammation, and alveolar simplification due to defective secondary septation, indicating that WNT/RYK signaling functions as an anti-inflammatory modulator in the lung mesenchyme [3]. In bone marrow stromal cells, downregulation of Ryk in mesenchymal stromal cells (MSCs) decreases their clonogenic activity and ability to support self-renewing expansion of primitive hematopoietic progenitors (HPCs) in response to canonical Wnt ligands [7].

In conclusion, Ryk is essential for multiple biological processes, including embryonic development, midgut elongation, lung development and homeostasis, and hematopoiesis-supporting activities. Studies using Ryk KO mouse models have revealed its significance in these processes and provided insights into diseases related to abnormal development, inflammation, and hematopoiesis-related disorders [1,2,3,7].