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BackgroundAutosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes PKD1 or PKD2 (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by PKHD1 (encoding fibrocystin/polyductin [FPC]). Primary cilia have been considered central to PKD pathogenesis due to protein localization and common cystic phenotypes in syndromic ciliopathies, but their relevance is questioned in the simple PKDs. ARPKD’s mild phenotype in murine models versus in humans has hampered investigating its pathogenesis.MethodsTo study the interaction between Pkhd1 and Pkd1, including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes.ResultsThe genetic interaction was synergistic in both species, with digenic animals exhibiting phenotypes of rapidly progressive PKD and early lethality resembling classic ARPKD. Genetic interaction between Pkhd1 and Pkd1 depended on dosage in the digenic murine models, with no significant enhancement of the monogenic phenotype until a threshold of reduced expression at the second locus was breached. Pkhd1 loss did not alter expression, maturation, or localization of the ADPKD polycystin proteins, with no interaction detected between the ARPKD FPC protein and polycystins. RNA-seq analysis in the digenic and monogenic mouse models highlighted the ciliary compartment as a common dysregulated target, with enhanced ciliary expression and length changes in the digenic models.ConclusionsThese data indicate that FPC and the polycystins work independently, with separate disease-causing thresholds; however, a combined protein threshold triggers the synergistic, cystogenic response because of enhanced dysregulation of primary cilia. These insights into pathogenesis highlight possible common therapeutic targets.

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Chronic inflammation is a common feature of aging and numerous diseases such as diabetes, obesity, and autoimmune syndromes and has been linked to the development of hematological malignancy. Blood-forming hematopoietic stem cells (HSC) can contribute to these diseases via the production of tissue-damaging myeloid cells and/or the acquisition of mutations in epigenetic and transcriptional regulators that initiate evolution toward leukemogenesis. We previously showed that the myeloid “master regulator” transcription factor PU.1 is robustly induced in HSC by pro-inflammatory cytokines such as interleukin (IL)-1β and limits their proliferative activity. Here, we used a PU.1-deficient mouse model to investigate the broader role of PU.1 in regulating hematopoietic activity in response to chronic inflammatory challenges. We found that PU.1 is critical in restraining inflammatory myelopoiesis via suppression of cell cycle and self-renewal gene programs in myeloid-biased multipotent progenitor (MPP) cells. Our data show that while PU.1 functions as a key driver of myeloid differentiation, it plays an equally critical role in tailoring hematopoietic responses to inflammatory stimuli while limiting expansion and self-renewal gene expression in MPPs. These data identify PU.1 as a key regulator of “emergency” myelopoiesis relevant to inflammatory disease and leukemogenesis.