LIY Deletion in SH2 Domain Alters STAT5A Function and Disrupts Mammary Gland Development and circRNA Expression

Ethan McCrary

Mentor: Dr. Markus Hoffmann, Biomedical Graduate Education, Georgetown University Medical Center.

Date/Time: April 28th, 2026 at 12:00 PM.

Abstract: Mammary gland development during pregnancy is regulated by lactogenic hormones acting through the JAK2–STAT5 signaling pathway. STAT5 is activated via JAK-mediated phosphorylation and subsequent binding to the SH2 domain. In this study, we introduced a LIY (leucine-isoleucine-tyrosine) deletion within this domain, revealing significant functional effects. To investigate the consequences of this mutation, mammary tissue was collected at lactation day 1 (L1) and pregnancy day 18 (P18). The lack of LIY in the SH2 domain resulted in the inability for female mice to feed their pups. Histological analysis revealed underdeveloped mammary glands in mutant mice. A transcriptomic analysis showed that the L1 LIY samples clustered more closely with P18 groups than with L1 wildtype (WT) controls. At both time points, LIY samples exhibited significant downregulation of circular RNAs derived from milk protein genes, WAP and CSN, alongside upregulation of genes associated with transcriptional regulation. Gene set enrichment analysis showed significant enrichment in organ and tissue development pathways in the P18 RNA-seq data. Analysis of circRNA profiles revealed similar patterns. Collectively, these findings indicate that the LIY deletion alters the function of STAT5, disrupts mammary gland development, and highlights a potential role for STAT5 in the regulation of circular RNAs.