A dog carrying mutations in AVP-NPII exhibits key features of central diabetes insipidus

Central diabetes insipidus(CDI)is a rare disease characterized by the excretion of copious amounts of diluted urine(polyuria),excess water intake(polydipsia),and a rise in serum sodium concentration(hypernatremia)(Christ-Crain et al.,2019).The neuropeptide arginine-vasopressin(AVP)is synthesized as a preprohormone along with its carrier protein neurophysin II(NPII)in hypothalamic supraoptic(SON)and paraventricular(PVN)magnocellular neurons,stored in the posterior pituitary,and secreted into the circulation.

Drosophila homolog of the intellectual disability-related long-chain acyl-CoA synthetase 4 is required for neuroblast proliferation

Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic X-linked intellectual disability (ID). However, the neural functions of ACSL4 and how loss of ACSL4 leads to ID remain largely unexplored. We report here that mutations in Acsl, the Drosophila ortholog of human ACSL3 and ACSL4, result in developmental defects of the mushroom body (MB), the center of olfactory learning and memory. Specifically, Acsl mutants show fewer MB neuroblasts (Nbs) due to reduced proliferation activity and premature differentiation. Consistently, these surviving Nbs show reduced expression of cyclin E, a key regulator of the G1-to S-phase cell cycle transition, and nuclear mislocalization of the transcriptional factor Prospero, which is known to repress self-renewal genes and activate differentiating genes. Furthermore, RNA-seq analysis reveals downregulated Nb-and cell-cyclerelated genes and upregulated neuronal differentiation genes in Acsl mutant Nbs. As Drosophila Acsl and human ACSL4 are functionally conserved, our findings provide novel insights into a critical and previously unappreciated role of Acsl in neurogenesis and the pathogenesis of ACSL4-related ID.

Drosophila Homolog of FMRP Maintains Genome Integrity by Interacting with Piwi

Fragile X syndrome （FraX）, the most common form of inherited mental retardation, is caused by the absence of the evolutionally conserved fragile X mental retardation protein （FMRP）. While neuronal functions of FMRP have been intensively studied for the last two decades, its role in non-neuronal cells remains poorly understood. Piwi, a key component of the Piwi-interacting RNA （piRNA） pathway, plays an essential role in germline development. In the present study, we report that similar to piwi, dfmrl, the Drosophila homolog of human FMR1, is required for transposon suppression in the germlines. Genetic analyses showed that dfmrl and piwi act synergistically in heterochromatic silencing, and in inhibiting the differentiation of primordial germline cells and transposon expression. Northern analyses showed that roo piRNA expression levels are reduced in dfmrl mutant ovaries, suggesting a role of dfmrl in piRNA biogenesis. Biochemical analysis demonstrated a physical interaction between dFMRP and Piwi via their N-termini. Taken together, we propose that dFMRP cooperates with Piwi in maintaining genome integrity by regulating heterochromatic silencing in somatic cells and suppressing transposon activity via the piRNA pathway in germlines.

Dogs lacking Apolipoprotein E show advanced atherosclerosis leading to apparent clinical complications

Atherosclerotic cardiovascular disease resulting from dysregulated lipid metabolism is the leading cause of morbidity and mortality worldwide.Apolipoprotein E(ApoE)plays a critical role in cholesterol metabolism.Knockouts in lipid-metabolizing proteins including ApoE in multiple model organisms such as mice and rats exhibiting elevated levels of cholesterol have been widely used for dissecting the pathology of atherosclerosis,but few of these animal models exhibit advanced atherosclerotic plaques leading to ischemia-induced clinical symptoms,limiting their use for translational studies.Here we report hypercholesterolemia and severe atherosclerosis characterized by stenosis and occlusion of arteries,together with clinical manifestations of stroke and gangrene,in ApoE knockout dogs generated by CRISPR/Cas9 and cloned by somatic cell nuclear transfer technologies.Importantly,the hypercholesterolemia and atherosclerotic complications in F0 mutants are recapitulated in their offspring.As the ApoE-associated atherosclerosis and clinical manifestations in mutant dogs are more similar to that in human patients compared with those in other animal models,these mutant dogs will be invaluable in developing and evaluating new therapies,including endovascular procedures,against atherosclerosis and related disorders.