Identification of Novel Isoforms of Activin Receptor-Like Kinase 7 (ALK7) Generated by Alternative Splicing and Expression of ALK7 and Its Ligand, Nodal, in Human Placenta1

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Abstract
Members of the transforming growth factor (TGF) β family play critical roles in regulating placental functions. Using polymerase chain reaction (PCR)-based strategies, we have cloned four transcripts encoding full-length activin receptor-like kinase 7 (ALK7) and three novel ALK7 isoforms from the human placenta. The full-length ALK7 has 493 amino acids and exhibits all characteristics of TGFβ type I receptors, including an activin receptor-binding domain, a transmembrane domain, a GS domain, and a serine/threonine kinase domain. The three ALK7 isoforms identified include a truncated ALK7 (tALK7) and two soluble proteins designated as soluble ALK7a (sALK7a) and soluble ALK7b (sALK7b). The tALK7 lacks the first 50 amino acids of the full-length ALK7, resulting in a truncated receptor-binding domain. Both sALK7a and sALK7b lack transmembrane and GS domains. The ALK7 gene, located on chromosome 2q24.1, is composed of at least nine exons and eight introns. The isoforms of ALK7 are generated by alternative splicing. Transcripts encoding the sALK7 isoforms differ from the full-length transcript by lacking exon III or both exons III and IV in sALK7a and sALK7b, respectively. The transcript for tALK7 uses an alternative exon located within the first intron of the full-length transcript. These results indicate that four distinct proteins are encoded by the human ALK7 gene. Both reverse transcription-PCR and Western blot analysis showed that ALK7 and its isoforms are expressed in human placentae of different stages of pregnancy and that their expression is developmentally regulated. In addition, mRNA expression of Nodal, a ligand for ALK7, was also detected in placentae of different gestational age. The role of Nodal and ALK7 in human placenta is currently under investigation.