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Piol et al. uncover that impaired eukaryotic initiation factor 5a (Eif5a) hypusination disrupts axonal translation and neuronal activity in fused in sarcoma-amyotrophic lateral sclerosis (FUS-ALS) by applying spatial transcriptomics in motor axons. In vitro and in vivo targeting Eif5a hypusination via spermidine supplementation improves ALS model phenotypes.

Blanpain and colleagues delineate lineage reprogramming following PTEN deletion in different prostate cancer-originating cells, demonstrating that in basal cells the NF-κB pathway and innate immunity control stem cell plasticity and tumor initiation.

The mechanisms regulating multipotency in glandular epithelia remain unclear. Here, the authors identify the key role of collagen signaling and ECM stiffness in regulating stem cell multipotency in glandular epithelia.

Resident macrophages of the muscularis externa refine the enteric nervous system (ENS) early in life by pruning synapses and phagocytosing enteric neurons, and later switch to a neuro-supportive function, indicating that the ENS is governed by a dedicated population of resident macrophages that adapt to the timely needs of the ENS.

The multipotency of basal stem cells is directly regulated by luminal cells through the secretion of TNF, and, following luminal cell ablation, the Notch, Wnt and EGFR signalling pathways reactivate basal cell multipotency.

Calcium imaging of the mouse jejunum shows that specific nutrients in the intestinal lumen are detected by epithelial cells, which activate specific sets of enteric neurons through a serotonin-mediated signalling process.

Wuidart et al. show that the mammary gland develops from embryonic multipotent progenitors that switch from multipotency to unipotency and express a unique gene signature. ΔNp63 promotes their basal fate and also reprograms adult luminal cells.

By fusing genomic data, the eXtasy tool effectively prioritizes rare human exomic sequence variants as causal disease variants.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

Experiments in mice show that expression of the oncogene SmoM2 induces basal cell carcinoma in the ear epidermis but not in the back skin, and that this difference in susceptibility is regulated by the extracellular matrix.

Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.

Netrin-1 is upregulated in cancer models that undergo spontaneous epithelial-to-mesenchymal transition, and its targeting blocks the progression of tumour cells to a late mesenchymal state, suggesting possible therapeutic applications.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations.

Epithelial-to-mesenchymal transition in tumour cells occurs through distinct intermediate states, associated with different metastatic potential, cellular properties, gene expression, and chromatin landscape

Single-cell analysis in a mouse model of skin stretching shows that stretching causes a transient expansion bias in a population of epidermal stem cells, which is associated with chromatin remodelling and changes in transcriptional profiles.

Analysis of rare de novo mutations in gene regulatory elements suggests that 1–3% of patients with neurodevelopmental disorders carry such mutations in elements that are active in the fetal brain.

In this Review, the authors discuss the latest advances in profiling multiple molecular modalities from single cells, including genomic, transcriptomic, epigenomic and proteomic information. They describe the diverse strategies for separately analysing different modalities, how the data can be computationally integrated, and approaches for obtaining spatially resolved data.

Matthew Hurles, David FitzPatrick and colleagues report the discovery of four novel Mendelian disorders based on their analysis of exome sequence data from 4,125 families with diverse rare developmental disorders. They present their analytical pipeline as a general strategy for the discovery of genetic causes of autosomal recessive disorders.

Joris Vermeesch, Raoul Hennekam and colleagues show that missense mutations in the SWI/SNF family member gene SMARCA2 cause Nicolaides-Baraitser syndrome, a disorder characterized by sparse hair, distinctive facial morphology, distal limb anomalies and intellectual disability. The mutations cluster to sequences encoding ultra-conserved motifs in the catalytic ATPase region of the protein and likely act in a dominant-negative or gain-of-function fashion.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.