MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression post-transcriptionally. While many miRNA genes have been identified in mammals, the pathways regulating their production are not well understood. This study shows that a large fraction of miRNA genes are regulated post-transcriptionally. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are present at high levels but are not processed by Drosha. Analysis of tumor gene expression indicates that the widespread downregulation of miRNAs in cancer is due to a failure at the Drosha processing step. These findings reveal a novel regulatory step in miRNA function and provide a mechanism for miRNA downregulation in cancer. The study also shows that miRNA maturation is a regulated process. The biogenesis of miRNAs begins with a primary transcript (pri-miRNA), which is processed by Drosha to form a precursor (pre-miRNA), then by Dicer to generate the mature miRNA. This mature miRNA is loaded into the RNA-induced silencing complex (RISC) to mediate target mRNA translational suppression. The study found that a large fraction of miRNAs is regulated during the Drosha processing step, which has a major impact on miRNA expression during embryonic development and in cancer. The study analyzed the expression of miRNAs during mouse development and found that the Let-7 family miRNAs are highly expressed at 10.5 days of gestation. The primary transcript of Let-7g is highly expressed throughout development, but the mature miRNA is not detected in embryonic stem (ES) cells. This suggests that processing of Let-7g is blocked at the Drosha step. The study also found that the processing of other miRNA genes is regulated at the Drosha step, with some miRNAs showing a correlation between primary transcript and mature miRNA expression, while others do not. The study also found that the downregulation of miRNAs in cancer is likely due to a failure at the Drosha processing step. Analysis of existing expression data showed that tumor samples had overall reduction in miRNA expression levels, which was not due to misregulated transcription. The study suggests a multistep model for the control of miRNA expression, with transcription of the pri-miRNA and processing at the Dicer step being regulated. Further suppression of miRNA production is achieved at the Drosha step, which may be necessary for early development to prevent inappropriate expression of even small amounts of Let-7, which could promote differentiation with disastrous consequences. The study also highlights the importance of miRNAs in cancer, as their downregulation may lead to increased expression of oncogenes such as Ras, promoting tumor cell survival. The study provides new insights into the regulation of miRNA expression and its implications for cancer.MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression post-transcriptionally. While many miRNA genes have been identified in mammals, the pathways regulating their production are not well understood. This study shows that a large fraction of miRNA genes are regulated post-transcriptionally. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are present at high levels but are not processed by Drosha. Analysis of tumor gene expression indicates that the widespread downregulation of miRNAs in cancer is due to a failure at the Drosha processing step. These findings reveal a novel regulatory step in miRNA function and provide a mechanism for miRNA downregulation in cancer. The study also shows that miRNA maturation is a regulated process. The biogenesis of miRNAs begins with a primary transcript (pri-miRNA), which is processed by Drosha to form a precursor (pre-miRNA), then by Dicer to generate the mature miRNA. This mature miRNA is loaded into the RNA-induced silencing complex (RISC) to mediate target mRNA translational suppression. The study found that a large fraction of miRNAs is regulated during the Drosha processing step, which has a major impact on miRNA expression during embryonic development and in cancer. The study analyzed the expression of miRNAs during mouse development and found that the Let-7 family miRNAs are highly expressed at 10.5 days of gestation. The primary transcript of Let-7g is highly expressed throughout development, but the mature miRNA is not detected in embryonic stem (ES) cells. This suggests that processing of Let-7g is blocked at the Drosha step. The study also found that the processing of other miRNA genes is regulated at the Drosha step, with some miRNAs showing a correlation between primary transcript and mature miRNA expression, while others do not. The study also found that the downregulation of miRNAs in cancer is likely due to a failure at the Drosha processing step. Analysis of existing expression data showed that tumor samples had overall reduction in miRNA expression levels, which was not due to misregulated transcription. The study suggests a multistep model for the control of miRNA expression, with transcription of the pri-miRNA and processing at the Dicer step being regulated. Further suppression of miRNA production is achieved at the Drosha step, which may be necessary for early development to prevent inappropriate expression of even small amounts of Let-7, which could promote differentiation with disastrous consequences. The study also highlights the importance of miRNAs in cancer, as their downregulation may lead to increased expression of oncogenes such as Ras, promoting tumor cell survival. The study provides new insights into the regulation of miRNA expression and its implications for cancer.