Biology subjects

Stevanovic, K.

Publications and source records attributed to Stevanovic, K..

3 recordsLinked to original sources

bioRxiv2026

Intermittent exposure to high ambient heat during the second half of gestation in mice causes mild alterations of reproductive endpoints in male embryos

Periods of elevated ambient temperature challenge the bodys ability to maintain internal homeostasis, and heat stress poses particular risks during pregnancy. Epidemiological studies associate gestational heat exposure with higher rates of congenital anomalies such as hypospadias, yet the direct link between gestational heat exposure and reproductive anomalies remains unknown. In this study, we examined the effects of intermittent heat exposure on reproductive development in male mouse offspring. Pregnant dams either remained at constant temperature of 22{degrees}C (control) or were exposed to 38{degrees}C for 2 hours daily (experimental) from embryonic day (E)10 to E18, modeling intermittent heat exposure during mid-to-late gestation. Embryos were collected at E18 for analysis. While heat exposure did not affect pregnancy outcomes, including placental development, litter size, sex ratio, or fetal growth, male embryos exhibited significantly reduced anogenital distance and increased hypospadias scores, which are both markers of disrupted androgen signaling. Despite these phenotypic changes, expression of genes involved in androgen synthesis in the fetal testis, as well as gene expression in external genitalia, remained unchanged. Instead, transcriptomic analysis revealed significant alterations in testicular pathways related to RNA splicing and mRNA processing. Together, these findings reveal that maternal heat stress disrupts reproductive development of male offspring, with altered gene regulatory processes being a potential driver.

developmental biology↗

bioRxiv2021

Numb reduces Tau levels and prevents neurodegeneration in mouse models of tauopathy in an isoform-specific manner

Accumulation of the microtubule-associated protein Tau is linked to neuronal cell death in tauopathies, but how exactly intraneuronal Tau levels are regulated in health and disease remains unclear. Here we identify the trafficking adaptor protein Numb as an essential regulator of Tau homeostasis. Conditional inactivation of Numb in retinal ganglion cells (RGCs) increases monomeric and oligomeric Tau levels, leading to axonal blebbing followed by neuronal cell loss in aged mice. Moreover, in a mouse model of tauopathy, inactivation of Numb in RGCs and spinal motoneurons accelerates neurodegeneration, and leads to precocious hindlimb paralysis. Conversely, overexpression of the long isoform of Numb (Numb-72), but not other isoforms, decreases intracellular Tau levels by promoting the extracellular release of monomeric Tau, and AAV-mediated delivery of Numb-72 in RGCs in vivo prevents neurodegeneration in two different mouse models of tauopathy. Taken together, these results uncover Numb as a modulator of intracellular Tau levels and identify Numb-72 as a novel therapeutic factor for tauopathies.

neuroscience↗

bioRxiv2020

Mutations on a novel brain-specific isoform of PGC1α leads to extensive upregulation of neurotransmitter-related genes and sexually dimorphic motor deficits in mice

The peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1) is known as a transcriptional co-activator in peripheral tissues but its function in the brain remains poorly understood. Various brain-specific Pgc1 isoforms have been reported in mice and humans, including transcripts derived from a novel promoter about [~]580 Kb upstream from the reference gene. These isoforms incorporate repetitive sequences from the simple sequence repeat (SSR) and short interspersed nuclear element (SINE) classes and are predicted to give rise to proteins with distinct amino-termini. In this study, we show that a SINE-containing isoform is the predominant form of Pgc1 expressed in neurons. We then generated a mouse carrying a mutation within the SINE to study its functional role in the brain. By combining genomics, biochemical and behavioural approaches, we show that this mutation leads to impaired motor coordination in females, but not male mice, associated with the upregulation of hundreds of cerebellar genes. Moreover, our analysis suggests that known nuclear receptors interact with this isoform of PGC1 in the brain to carry out the female transcriptional program. These data expand our knowledge on the role of Pgc1 in the brain and help explain its conflicting roles in neurological disease and behavioural outcomes.

neuroscience↗