Fig. 6

Proposed model illustrating domain specific functions of Gon4la in post-embryonic growth regulation. (A) WT scenario: Full-length WT Gon4la utilizes its N-terminal YY1-binding domain (N-YBD) and putative transactivation domain (TD) (solid red arrow) to regulate endocrine signaling (e.g., hepatic Igf1a production for skeletal development). Its C-terminal PAH and SANT domains (solid blue arrow) are crucial for metabolic organ homeostasis (e.g., intestinal integrity, pancreatic exocrine cell differentiation), collectively supporting normal post-embryonic growth. (B) gon4la mutant scenarios: (a) gon4laⁿⁿ²¹¹² (complete loss of N-YBD, TD, PAH, and SANT domains): this severe truncation prevents YY1 interaction and leads to impaired hepatic igf1a production, delayed skeletal development, and increased mortality; (b) gon4laⁿⁿ²¹²³ (retention of partial N-YBD but loss of TD, PAH, and SANT domains): this mutant shows an intermediate reduction in igf1a levels and skeletal abnormalities, potentially due to the retaining N-YBD capacity; (c) gon4laⁿⁿ²¹³¹ (retention of N-YBD and TD but loss of PAH and SANT domains): this mutant exhibits the least severe endocrine disruption, with igf1a levels comparable to WT. Notably, the bone mineral density (BMD) is decreased in gon4laⁿⁿ²¹¹² (light gray skeleton) and gon4laⁿⁿ²¹²³ (gray skeleton), while BMD of gon4laⁿⁿ²¹³¹ (black skeleton) remains comparable to WT. All three mutants lacking PAH/SANT domains, display significant intestinal and pancreatic abnormalities, including increased progenitor proliferation and defective differentiation. This underscores the role of these C-terminal domains in metabolic organ function. Because a mutant specifically lacking only the N-YBD or TD (while retaining PAH/SANT) was not generated, potential contributions of Gon4la’s N-YBD or TD to metabolic organ homeostasis (dotted black arrows) cannot be completely ruled out. Cellular phenotypes depicted: Goblet cells (matured vs. fewer vesicles), enteroendocrine cells (matured vs. less matured), prmt1⁺ progenitor cells, enterocytes, and acinar cells (normal vs. fewer zymogen granules). Expression domain of Gon4la protein in intestinal folds is indicated by the U-shaped magenta line. Arrow/Line key: Solid red arrow = positive regulation by N-YBD/TD on the endocrine system or metabolic organs; faint red arrow = weakened positive regulation; solid blue arrow = positive regulation by PAH/SANT domains on metabolism. This figure is created with BioRender.com.