Fibroblast growth factor (FGF)/extracellular signal-regulated kinase (ERK) signaling plays a crucial role in anterior–posterior (A–P) axial patterning of vertebrate embryos by promoting posterior development. In our screens for novel developmental regulators in Xenopus embryos, we identified Fam3b as a secreted factor regulated in ectodermal explants. Family with sequence similarity 3 member B (FAM3B)/PANDER (pancreatic-derived factor) is a cytokine involved in glucose metabolism, type 2 diabetes, and cancer in mammals. However, the molecular mechanism of FAM3B action in these processes remains poorly understood, largely because its receptor is still unidentified. Here we uncover an unexpected role of FAM3B acting as a FGF receptor (FGFR) ligand in Xenopus embryos. fam3b messenger RNA (mRNA) is initially expressed maternally and uniformly in the early Xenopus embryo and then in the epidermis at neurula stages. Overexpression of Xenopus fam3b mRNA inhibited cephalic structures and induced ectopic tail-like structures. Recombinant human FAM3B protein was purified readily from transfected tissue culture cells and, when injected into the blastocoele cavity, also caused outgrowth of tail-like structures at the expense of anterior structures, indicating FGF-like activity. Depletion of fam3b by specific antisense morpholino oligonucleotides in Xenopus resulted in macrocephaly in tailbud tadpoles, rescuable by FAM3B protein. Mechanistically, FAM3B protein bound to FGFR and activated the downstream ERK signaling in an FGFR-dependent manner. In Xenopus embryos, FGFR activity was required epistatically downstream of Fam3b to mediate its promotion of posterior cell fates. Our findings define a FAM3B/FGFR/ERK-signaling pathway that is required for axial patterning in Xenopus embryos and may provide molecular insights into FAM3B-associated human diseases.

成纤维细胞生长因子 (FGF)/细胞外信号调节激酶 (ERK) 信号传导通过促进后部发育在脊椎动物胚胎的前后 (​​A-P) 轴向模式中起着至关重要的作用。在我们筛选非洲爪蟾胚胎中新的发育调节因子时，我们将 Fam3b 鉴定为外胚层外植体中调节的分泌因子。具有序列相似性的家族 3 成员 B (FAM3B)/PANDER（胰源性因子）是一种参与葡萄糖代谢、2 型糖尿病和哺乳动物癌症的细胞因子。然而，FAM3B 在这些过程中作用的分子机制仍然知之甚少，主要是因为它的受体仍未确定。在这里，我们发现了 FAM3B 在非洲爪蟾胚胎中作为 FGF 受体 (FGFR) 配体的意外作用。家庭3b信使 RNA (mRNA) 最初在非洲爪蟾早期胚胎中以母体形式均匀表达，然后在神经胚阶段在表皮中表达。非洲爪蟾 fam3b mRNA的过表达抑制头部结构并诱导异位尾状结构。重组人 FAM3B 蛋白很容易从转染的组织培养细胞中纯化出来，当注入囊胚腔时，也会导致尾部结构的生长，而牺牲前部结构，表明 FGF 样活性。非洲爪蟾中特异性反义吗啉代寡核苷酸对fam3b的消耗导致尾芽蝌蚪的大头畸形，可通过 FAM3B 蛋白抢救。从机制上讲，FAM3B 蛋白与 FGFR 结合并以 FGFR 依赖的方式激活下游 ERK 信号。在非洲爪蟾胚胎中，FGFR 活性需要在 Fam3b 的上位下游来介导其对后细胞命运的促进。我们的研究结果定义了非洲爪蟾胚胎轴向模式所需的 FAM3B/FGFR/ERK 信号通路，并可能提供对 FAM3B 相关人类疾病的分子见解。