Fgf16, a member of the FGF superfamily, was discovered in 1998 in human and rat heart samples. As a component of the FGF9 subfamily of ligands, it is functionally conserved in vertebrates and can rescue invertebrate loss-of-function phenotypes [1]. It has a broad expression pattern in tissues like brown adipose tissue, heart, brain, and others, playing roles in stem cell maintenance, proliferation, cell fate specification, and metabolism [1].

Loss-of-function experiments have shown diverse roles of Fgf16. In zebrafish, knockdown of fgf16 decreased cell proliferation in the forebrain and midbrain, was essential for ventral telencephalon and diencephalon development, and for the specification of GABAergic neurons and oligodendrocytes in the forebrain [4]. In zebrafish pectoral fin bud formation, Fgf16 knockdown led to no fin bud outgrowth, as it is required for cell proliferation and differentiation in fin bud mesenchyme and AER respectively [5]. In mice, Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration; knockdown of Mettl3 increased cardiomyocyte proliferation and heart regeneration, while its overexpression decreased these processes by negatively regulating Fgf16 mRNA [2]. In a familial atrial septal defect study, the GATA4T280M mutation obstructed GATA4 occupancy at the FGF16 promoter, leading to impaired FGF16 transcription and cardiomyocyte proliferation defect, which could be rescued by FGF16 overexpression [3]. In breast cancer cells, FGF16 promotes invasion by reprogramming glucose metabolism via PFKFB4 [6].

In conclusion, Fgf16 is crucial for multiple biological processes including embryonic development, tissue regeneration, and metabolism. Gene knockout and related models have revealed its significance in diseases such as congenital heart defects, heart regeneration-related disorders, and certain cancers, providing insights into disease mechanisms and potential therapeutic targets.