Expression of the alpha 1(II) procollagen gene is not confined to chondrogenic tissues during vertebrate development. Transcripts of the human gene (COL2A1) are alternatively spliced to give mRNAs which either exclude (type IIB mRNA) or include (type IIA mRNA) an exon encoding a cysteine-rich domain in the amino-propeptide. The distribution of COL2A1 mRNAs in 27- to 44-day human embryos and 8- to 24-week fetuses was studied by in situ hybridization and RNase protection analyses. Type IIA mRNAs were expressed in prechondrogenic cells and were also preferentially expressed in chondrogenic tissues at regions of chondrocyte commitment and cartilage growth. During maturation of chondrocytes, there is a switch to expression of type IIB mRNAs. In non-chondrogenic tissues of early embryos, type IIA mRNA expression was associated with active tissue remodeling, epithelial organization, and sites of tissue interaction. Type IIA mRNAs were also expressed in some non-chondrogenic tissues where expression had previously been undetected, such as the tooth bud, liver, adrenal cortex, apical ectodermal ridge, and indifferent gonad. In older fetuses type IIA mRNAs were the sole or major transcript in most non-chondrogenic tissues except the choroid plexus and tendon. In the meninges there was a unique switch from type IIB to type IIA expression. The expression pattern of COL2A1 transcripts suggests that, in addition to contributing to the structural integrity of the cartilage extracellular matrix, type II procollagen may serve a morphogenetic role in embryonic development. Our findings clearly show that the pattern of expression of type II procollagen mRNAs is largely conserved between man and mouse. However, some differences exist, and these should be taken into consideration when animal models are used to study human diseases associated with COL2A1.