BMP Signaling Regulates Germ Cell Pluripotency, Sexual Differentiation, and Cancer Susceptibility

Testicular germ cell tumors are the most common malignancy found in young men between the ages of 14-40. While these tumors are highly curable with cisplatin based combined chemotherapies, the treatments come with very detrimental side effects and ultimately fail in up to 15% of patients. These patients have no other avenues of treatment and often times succumb to the disease. Very little is currently known about the biology of the tumors but risk factors highlight possible mechanisms of action. For example, patients with Disorders of Sex Development (DSD) have increased risk for developing malignant germ cell tumors. DSDs manifest at birth and present with atypical gonadal or anatomical sex as well as chromosomal aberrations[1, 2]. Some cases are explained by the presence of chromosomal aberrations, but the cause of many others remains unknown. Such syndromes thus highlight the potential links between germ cell pluripotency, sexual differentiation and cancer susceptibility. A recent GWAS study [3] identified association of BMP7 with testicular dysgenesis syndrome; however the molecular mechanisms behind this association remain unknown. Previously, we described the development of testicular germ cell tumors in zebrafish carrying a mutation in bmpr1bb, a BMP family receptor, and demonstrated that human GCTs have defects in BMP signaling. Here I use this model and next-generation sequencing analysis in a cross-species comparative oncology approach to identify genes and pathways with fundamental importance to the development of the human disease. I further defined the role of specific BMP ligands in mediating germ cell differentiation and identified reciprocal somatic- and germ cell BMP signaling events that regulate germ cell differentiation and maturation. Using genetic crosses to further impair BMP signaling, I found that zebrafish doubly heterozygous for mutations in bmpr1bb and bmp2b, bmp7a or smad5 have profoundly impaired gonadogenesis and altered male:female sex ratios. Affected fish also exhibit markedly abnormal gonadal differentiation, including the presence of undifferentiated gonadal tissue and the occurrence of biphenotypic gonads, as well as greatly increased germ cell tumor susceptibility. Our findings implicate defective BMP pathway signaling as a potential factor in DSDs and GCT susceptibility. Our goals are to identify biological mechanisms that govern germ cell differentiation and to understand how defects in this process cause human disease.