Chatti, K. | bioRxiv Science

bioRxiv2024

Impaired ovarian development in a zebrafish fmr1 knockout model

Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder and the leading genetic cause of autism spectrum disorders. FXS is caused by loss of function mutations in Fragile X mental retardation protein (FMRP), an RNA binding protein that is known to regulate translation of its target mRNAs, predominantly in the brain and gonads. The molecular mechanisms connecting FMRP function to neurodevelopmental phenotypes are well understood. However, neither the full extent of reproductive phenotypes, nor the underlying molecular mechanisms have been as yet determined. Here, we developed new fmr1 knockout zebrafish lines and show that they mimic key aspects of FXS neuronal phenotypes across both larval and adult stages. Results from the fmr1 knockout females also showed that altered gene expression in the brain, via the neuroendocrine pathway contribute to distinct abnormal phenotypes during ovarian development and oocyte maturation. We identified at least three mechanisms underpinning these defects, including altered neuroendocrine signaling in sexually mature females resulting in accelerated ovarian development, altered expression of germ cell and meiosis promoting genes at various stages during oocyte maturation, and finally a strong mitochondrial impairment in late stage oocytes from knockout females. Our findings have implications beyond FXS in the study of reproductive function and female infertility. Dissection of the translation control pathways during ovarian development using models like the knockout lines reported here may reveal novel approaches and targets for fertility treatments. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/579749v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@15ea8b3org.highwire.dtl.DTLVardef@195838corg.highwire.dtl.DTLVardef@ef8940org.highwire.dtl.DTLVardef@1bd58a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

molecular biology↗

bioRxiv2023

New insights into iodide metabolism based on preclinical models: impact on radiotherapy efficacy and protection against radioactive iodine exposure.

BackgroundThe main basic aspects of the regulation of thyroid metabolism by iodine are known, but given the complexity of the mechanisms involved, further analyzes in living animals are still required. Here, we provided new insights into iodine physiology but also into the optimization of radiotherapy with iodine, as well as effective countermeasures in the case of an exposure to radioactive iodine. MethodsWe performed Single Photon Emission Computed Tomography (SPECT) coupled to an X-ray scanner to record radiotracers in living mice and rats. Our imaging system was similar to that routinely used in nuclear medicine but was specifically designed for studies with small animals. Different modalities of administration of radioactive iodine or its radioactive analogues combined with a low or high iodine diet have been studied in pregnant, lactating and control animals. To optimize countermeasures against acute or chronic iodine exposure, the protective effects of potassium iodide (KI) administration protocols were analyzed. Perchlorate was administered to study the iodine metabolism in the kidney and stomach. ResultsOur results showed how the various organs capable of iodine uptake adapt to an iodine-deficient diet. Indeed, the uptake capacity of the thyroid gland, but also that of the salivary glands was significantly increased on a low iodine diet. In contrast, the iodine uptake capacity of the thyroid and lactating mammary glands was reduced on an iodide-rich diet. Our results also showed the physiological role of the kidneys in controlling excess circulating iodide. In addition, they revealed an active iodine cycle in the stomach. We also investigated the protective effects of daily KI administration during radioactive iodine exposure and found that the overall protection was better in rats (85%) than in mice (65%). We also included pregnant females and newborns, and we revealed the existence of specific mechanisms for the inhibition of the fetal thyroid by circulating iodine. Indeed, an iodine-rich diet or repeated daily administration of KI led to a strong inhibition of the iodide uptake capacity of the fetal thyroid. ConclusionsOur study contributes to a better understanding of iodine metabolism and its regulation in the thyroid and in non-thyroidal organs in adult, fetal and newborn animals. Extrapolated to humans, our results not only provide better understanding of iodide withdrawal as a clinical preparatory measure for patients with differentiated thyroid cancer, but also help to optimize countermeasures in the case of an exposure to radioactive iodine.

physiology↗