SummaryNeural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This “primary regionalization” allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS.

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we show that c-Maf regulates IL-10 production in CD4+ T cells in TH1 (malaria), TH2 (allergy) and TH17 (autoimmunity) disease models in vivo. Although CD4-targeted Maf-deficient mice showed greater pathology in TH1 and TH2 responses, TH17-mediated pathology was reduced, with accompanying decreased TH17 and increased Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription factor network, including enhanced NFAT activity, leading to the identification and validation of c-Maf as a negative regulator of IL-2. Decreased Rorc resulting from c-Maf deficiency was dependent on IL-2, explaining the in vivo observations. Thus, c-Maf is a positive and negative regulator of cytokine gene expression, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.

Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in the DAZ interacting protein 1-like (DZIP1L) gene in patients with ARPKD, findings we have further validated by loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and at the distal end of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. Consistent with a defect in the diffusion barrier, we found that the ciliary membrane translocation of the PKD proteins, polycystin-1 and −2, is compromised in DZIP1L mutant cells. Together, these data provide the first conclusive evidence that ARPKD is not a homogeneous disorder, and establishes DZIP1L as a second gene involved in its pathogenesis.

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