Probing Cell-Type Specificity of Mutant Phenotype at Transcriptomic Level Using Mosaic Analysis with Double Markers (MADM) Mosaic Analysis with Double Markers (MADM) represents a mouse genetic approach coupling differential fluorescent labeling to genetic manipulations in dividing cells and their lineages. MADM uniquely enables the generation and visualization of individual control or homozygous mutant cells in a heterozygous genetic environment. Among its diverse applications, MADM has been used to dissect cell-autonomous gene functions important for cortical development and neural development in general. The high cellular resolution offered by MADM also permits the analysis of transcriptomic changes of individual cells upon genetic manipulations. In this chapter, we describe an experimental protocol combining the generation and isolation of MADM-labeled cells with downstream single-cell RNA-sequencing technologies to probe cell-type specific phenotypes due to genetic mutations at single-cell resolution. 2886 139-151 139-151 Springer Nature 1