The Prrx1 gene, also known as Paired Related Homeobox 1, guides the body’s formation. Located on human chromosome 1, this gene belongs to a family of “homeobox genes,” fundamental in orchestrating development. Prrx1 encodes a protein that acts as a transcription coactivator, regulating other genes by enhancing the DNA-binding activity of proteins for growth and differentiation. This gene plays a significant role in shaping various body structures, expressing two isoforms.
Developmental Blueprint
During embryonic development, Prrx1 acts as a guiding force, ensuring structures form correctly. Its expression is primarily restricted to the mesoderm, the embryonic tissue layer that gives rise to connective tissues, muscles, and the circulatory system. This gene is particularly important for the precise patterning of limbs, including arms and legs. For instance, Prrx1 protein is found throughout the mesenchyme of the limb bud at early embryonic stages, around embryonic day 9.5 in mice, a period considered the beginning of the budding phase.
As development progresses, Prrx1’s influence extends to craniofacial structures, such as the skull and face. It is expressed in the cranial mesenchyme of facial prominences and is necessary for the formation of proximal first arch derivatives. In mice, a lack of both Prrx1 and its closely related gene, Prrx2, results in substantial defects in mesenchymal cell differentiation within the craniofacial region. These defects can manifest as malformations of the skull and lower jaw, including reduced or absent skull bones and cleft mandible.
Prrx1 also contributes to the development of the heart and great vessels. It is highly expressed in mesenchymal tissues within the developing cardiovascular system throughout embryogenesis. For example, Prrx1-deficient mice show abnormalities of the great vessels, including unusual positioning and curvature of the aortic arch, and misdirected ductus arteriosus. This gene’s involvement in epithelial-to-mesenchymal transition, a process where cells change their characteristics, is a feature of human cardiac development.
Regulating Tissue Identity
Beyond its initial role in embryonic patterning, Prrx1 continues to function in adult life, contributing to the maintenance and repair of various tissues. It plays a part in maintaining the identity and function of connective tissues, which include cartilage, bone, and ligaments. For instance, Prrx1 expression is observed in mesenchymal tissues in adult mice. Studies indicate that rare Prrx1-expressing cells act as stem cells for bone, white adipose tissue, and dermis in adult mice, indispensable for tissue homeostasis and repair.
Prrx1 is involved in tissue repair and regeneration processes. For example, in response to skin wounds, Prrx1-expressing cells migrate to the wound site and increase significantly during healing, participating in skin regeneration and reconstruction. These cells can contribute to subcutaneous tissue repair and the reconstruction of subcutaneous adipocytes and fascia. Prrx1 also contributes to bone regeneration after fractures.
Prrx1 can influence the differentiation of mesenchymal precursors. For example, it can inhibit the formation of fat cells (adipogenesis) by activating transforming growth factor-beta (TGF-beta) signaling. Prrx1 can also inhibit the differentiation of bone-forming cells (osteoblasts). This regulatory role helps maintain the specialized functions of adult tissues.
Prrx1 and Human Health
Dysfunction of Prrx1 can lead to various health consequences, particularly developmental disorders. Pathogenic variants in the PRRX1 gene are a cause of craniosynostosis, a condition where the bones of the skull fuse prematurely. This can result in abnormal head shape, sometimes requiring surgical intervention. Such variants can be inherited from unaffected relatives, indicating incomplete penetrance, meaning not everyone with the variant will develop the condition.
Prrx1 dysregulation is also associated with a rare and severe developmental condition called agnathia-otocephaly complex. This complex is characterized by severe malformations of the lower jaw (mandibular hypoplasia or agnathia), ear anomalies, and a small mouth opening with absence of the tongue. In mouse models, Prrx1 null mutations lead to microcephaly, low-set ears, a pointed snout, and large clefts of the secondary palate.
Abnormal Prrx1 expression links to certain disease processes in adults, such as fibrosis and some types of cancer. Fibrosis, which is the excessive formation of scar tissue, can be influenced by Prrx1. For example, Prrx1 is involved in idiopathic pulmonary fibrosis (IPF), where both its isoforms are upregulated in lung tissue and fibroblasts from IPF patients. Prrx1 modulates fibroblast proliferation, migration, and differentiation into myofibroblasts, cells that contribute to scar formation.
In cancer, Prrx1’s abnormal expression can contribute to disease progression. It has been identified as a transcription factor that drives the transformation of stromal fibroblasts into myofibroblasts, enhancing cancer aggressiveness. High Prrx1 expression in cancer-associated fibroblasts is linked to an unfavorable prognosis in various cancer types, including pancreatic ductal adenocarcinoma and uveal melanoma. Fibroblast-specific depletion of Prrx1 has shown promise in inducing remission in chemotherapy-resistant cancers in genetically engineered mouse models.