Biology subjects

Taylor, R. J.

Publications and source records attributed to Taylor, R. J..

9 recordsLinked to original sources

bioRxiv2026

Placental Insulin-like Growth Factor 1 Deficiency Drives Autism-Relevant Behavioral Changes with Sex-Specific Vulnerabilities

Preterm birth, placental insufficiency, and other perinatal adversities lead to the loss of placental support including critical hormones, such as Insulin-like growth factor 1 (IGF1), required for neurodevelopment. Decreased IGF1 and preterm birth are associated with neurodevelopmental disorder risk, including autism spectrum disorder. Whether placental Igf1 insufficiency drives neurodevelopmental risks is not understood. To understand these mechanisms, placental-targeted CRISPR manipulation in mice was employed to induce placental Igf1 insufficiency. Subsequently, embryonic forebrain development was assessed sex-specifically to identify structural, cellular, and transcriptomic changes. Postnatal offspring were used to determine neurobehavioral trajectories relevant to neurodevelopmental disorders as assessed through learning, motor, and affective behavioral tasks and neurostereology. Placental Igf1 insufficiency reduced embryonic forebrain growth, including decreased cell population across males and females. Embryonic forebrain transcriptomics revealed sex-specific alterations. Developmental pathways including insulin-like growth factor receptor signaling, laminin processes, and hormone synthesis were downregulated in male forebrain, driven by autism risk genes, Reln and Lama1. Altered genes in female forebrain were enriched for autism-risk genes including Grin2b and Dync1h1. Following these transcriptomic differences, postnatal neurobehavioral trajectories were sex-specific. Male offspring uniquely showed reduced motor learning, increased stereotyped behaviors, altered reversal learning, and reduced forebrain neuronal number. Female offspring displayed opposite behavioral changes as males and few changes in forebrain structure. Assessment of both adult male and female offspring forebrain white matter revealed an increased astrocyte population, a phenotype that appears similar to reactive astrogliosis seen in other models of preterm birth and placental insufficiency. The provision of Igf1 specifically from placenta is critical for offspring forebrain development. This temporary early deficit has persistent sex-specific neurobehavioral effects. These outcomes have relevance for neurodevelopmental disorder risk and highlight mechanisms that could facilitate intervention development for adverse outcomes after early loss of placental hormone support in perinatal adversity.

neuroscience↗

bioRxiv2025

Psychiatric risk implications of adolescent exposure to environmental insecticides: a systematic review of rodent studies

Adolescence is a sensitive period of neurodevelopment marked by remodeling of brain circuits that support cognitive development and emotion and behavior regulation. These maturation processes heighten psychiatric vulnerability to environmental exposures, including to toxicants such as insecticides. Epidemiological studies show widespread adolescent insecticide exposure and increasingly link this with psychiatric outcomes, yet underlying neural mechanisms remain poorly understood. Preclinical studies can clarify these associations and identify insecticide-induced mechanisms that may disrupt neurodevelopment and produce consequent long-term behavioral outcomes. Here, we performed a systematic review of rodent studies following PRISMA guidelines. 50 original articles met inclusion criteria, examining neurotoxic outcomes following insecticide exposure during adolescence (postnatal days 21-60). Outcomes were categorized into four domains: neurocognitive, neuropsychiatric, neurobiological, and general neurotoxicity. Risk of bias was assessed using the SYRCLE Risk of Bias tool. Across studies, insecticide exposure during adolescence led to learning and memory impairments and tended to increase depression relevant behaviors, alter locomotor activity, and produce general neurotoxic effects. Mechanistic findings highlighted disruptions in cholinergic and monoaminergic signaling, oxidative stress, neuroimmune changes, and cell death and other neurodegenerative processes. Together, these findings indicate adolescent insecticide exposure disrupts multiple neural systems with behavioral consequences relevant to adolescent development and psychiatric risk. Future research should model real-world exposures (e.g. dose, timing) to better inform translational understanding of adolescent psychiatric vulnerability. Because many life-long neuropsychiatric disorders emerge in adolescence, identifying how modifiable environmental exposures shape risk offers an opportunity for prevention and intervention strategies to alter the course of disease across the lifespan.

neuroscience↗

bioRxiv2025

The mechanistic basis of cargo selection during Golgi maturation

The multiple cisternae of the Golgi apparatus contain resident membrane proteins crucial for lipid and protein glycosylation. How Golgi residents remain in their designated compartments despite a constant flow of secretory cargo is incompletely understood. Here, we determined the structure of the COPI vesicle coat containing GOLPH3, an adaptor protein that binds the cytosolic tails of many Golgi residents. The structure, together with structure-guided mutagenesis and functional assays, reveals how GOLPH3 uses coincidence detection of COPI and lipid to engage Golgi residents preferentially at late cisternae. Our findings rationalize the logic of cisternal maturation and explain how COPI can engage different types of substrates in different Golgi cisternae to retrieve some proteins back to the ER while retaining others within the Golgi apparatus.

cell biology↗

bioRxiv2025

A dataset of adult heart and liver mass after placental Insulin-like growth factor 1 overexpression and partial knockout in mice

The placenta is an important producer of hormones essential for fetal development. Insulin-like growth factor 1 (IGF1) is a hormone primarily produced in the placenta in utero and is an important regulator of various developmental pathways including those in heart and liver. Embryonic disruptions in these developmental pathways can lead to lifelong changes and are often associated with chronic disease. Further, the placenta has sex-specific impacts on offspring development in response to hormonal changes. Previous work has shown that altered expression of Igf1 in the placenta results in sexually dimorphic changes to placental and fetal developmental outcomes. Here, mice underwent placental-targeted CRISPR manipulation for overexpression or insufficiency of Igf1. At the time of euthanasia, heart and liver tissues were collected and weighed. This dataset presents the heart and liver mass of these postnatal mice. There was a significant increase in proportional heart mass in placental Igf1 overexpression adult female mice and a trending increase in proportional liver mass in placental Igf1 overexpression adult male mice. No significant changes in heart or liver mass were seen in placental Igf1 insufficiency mice. These data provide insight into the impact of placental IGF1 on long-term heart and liver development. VALUE OF THE DATAO_LIThere is significant evidence for the role of early genetic changes in influencing long-term health outcomes, as laid out by the Developmental Origins of Health and Disease (DOHaD) hypothesis [1]. According to this hypothesis, genetic factors may be critical in determining the timing and severity of chronic disease, with varying effects based on sex. Genetics of the placenta, which makes up the maternal-fetal interface, plays an important role in modulating exposures associated with the DOHaD hypothesis [2]. C_LIO_LIThe placenta provides essential hormones to the fetus during pregnancy [3]. Placental changes are associated with the development of chronic disease and metabolic changes [4,5]. Disruptions in placental functions have been linked to defects including congenital heart disease which affects approximately 40,000 babies each year in the United States [6,7]. The placenta is also linked to metabolic diseases later in life such as nonalcoholic fatty liver disease, a chronic liver disease which has increased in prevalence by over 50% from 1990 to 2019 [5,8,9]. C_LIO_LIInsulin-like growth factor 1 (IGF1) is a placentally produced factor that regulates pathways involved in fetal growth and development and has been shown to be critical in growth of the heart and liver [10-13]. Despite the importance of the placenta and IGF1 in heart and liver growth, specific links between placental Igf1 expression and developmental outcomes remain understudied. C_LIO_LIPlacental function is known to have sex-specific impacts on fetal growth [14]. Further, Igf1 expression in the placenta is linked to differences in offspring developmental outcomes by sex [15]. Placental Igf1 overexpression and insufficiency affect offspring in a sexually dimorphic manner. IGF1 is a hormone and interacts with sex hormones, likely contributing to sex differences in response to changes in Igf1 expression [16]. Further research, including the work done to produce this dataset, may help clarify the role of placenta Igf1 expression in fetal outcomes, specifically regarding sex differences. C_LIO_LIThe data presented in this paper provide insight into the effects of placental Insulin-like growth factor 1 overexpression and insufficiency on adult heart and liver mass. More research is needed to understand specific functional impacts on these organs. Further, understanding the effects of placental genetic changes may support the development of future treatments and therapies for placental insufficiencies. C_LI

physiology↗

bioRxiv2025

Placental Igf1 Overexpression Sex-Specifically Impacts Mouse Placenta Structure, Altering Offspring Striatal Development and Behavior

Insulin-like growth factor 1 (IGF1) is produced primarily in the placenta in utero and is an essential hormone for neurodevelopment. Specifically, how placental IGF1 production persistently influences the brain is unclear. This study evaluated the effects of placental Igf1 overexpression on embryonic and postnatal brain development, particularly for striatum, a region highly linked to neurodevelopmental disorders. Placental Igf1 was overexpressed via placental-targeted CRISPR manipulation. This overexpression altered placenta structure and function distinctly in females and males. Early differences in placental function altered the trajectory of striatal development, as adult females showed persistent changes in striatal cell composition and striatal dependent behavior while males were less affected in brain and behavior outcomes. Overall, these results demonstrate that placental Igf1 expression alters striatal development and behavior in ways relevant to neurodevelopmental disorders. These findings expand our understanding of placental influence on neurodevelopment and will aid in identifying placental-targeted preventive interventions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/644829v1_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@22f53borg.highwire.dtl.DTLVardef@1120913org.highwire.dtl.DTLVardef@111c61forg.highwire.dtl.DTLVardef@1e6531d_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

F-BAR proteins CIP4 and FBP17 function in cortical neuron radial migration and process outgrowth

Neurite initiation from newly born neurons is a critical step in neuronal differentiation and migration. Neuronal migration in the developing cortex is accompanied by dynamic extension and retraction of neurites as neurons progress through bipolar and multipolar states. However, there is a relative lack of understanding regarding how the dynamic extension and retraction of neurites is regulated during neuronal migration. In recent work we have shown that CIP4, a member of the F-BAR family of membrane bending proteins, inhibits cortical neurite formation in culture, while family member FBP17 induces premature neurite outgrowth. These results beg the question of how CIP4 and FBP17 function in radial neuron migration and differentiation in vivo, including the timing and manner of neurite extension and retraction. Indeed, the regulation of neurite outgrowth is essential for the transitions between bipolar and multipolar states during radial migration. To examine the effects of modulating expression of CIP4 and FBP17 in vivo, we used in utero electroporation, in combination with our published Double UP technique, to compare knockdown or overexpression cells with control cells within the same mouse tissue of either sex. We show that either knockdown or overexpression of CIP4 and FBP17 results in the marked disruption of radial neuron migration by modulating neuronal morphology and neurite outgrowth, consistent with our findings in culture. Our results demonstrate that the F-BAR proteins CIP4 and FBP17 are essential for proper radial migration in the developing cortex and thus play a key role in cortical development. SIGNIFICANCE STATEMENTDuring embryonic development, radial migration of newly born cortical neurons is a complex process that underlies the proper formation of the neocortex, the outermost layers of neurons in the brain. Disruptions in radial migration results in profound effects on cognitive function and can lead to devastating developmental disabilities. To better understand this critical process in brain development we examined two members of the F-BAR family of membrane bending proteins, CIP4 and FBP17, which are present in the developing brain. We demonstrate that intracellular concentrations of these proteins must be tightly regulated. Increasing or decreasing levels of either protein has profound effects on neuronal morphology and proper radial migration, suggesting they are key players in cortical development.

neuroscience↗

bioRxiv2024

A Methodology for Specific Disruption of Microtubules in Dendritic Spines

Dendritic spines, the mushroom-shaped extensions along dendritic shafts of excitatory neurons, are critical for synaptic function and are one of the first neuronal structures disrupted in neurodevelopmental and neurodegenerative diseases. Microtubule (MT) polymerization into dendritic spines is an activity-dependent process capable of affecting spine shape and function. Studies have shown that MT polymerization into spines occurs specifically in spines undergoing plastic changes. However, discerning the function of MT invasion of dendritic spines requires the specific inhibition of MT polymerization into spines, while leaving MT dynamics in the dendritic shaft, synaptically connected axons and associated glial cells intact. This is not possible with the unrestricted, bath application of pharmacological compounds. To specifically disrupt MT entry into spines we coupled a MT elimination domain (MTED) from the Efa6 protein to the actin filament-binding peptide LifeAct. LifeAct was chosen because actin filaments are highly concentrated in spines and are necessary for MT invasions. Temporally controlled expression of this LifeAct-MTED construct inhibits MT entry into dendritic spines, while preserving typical MT dynamics in the dendrite shaft. Expression of this construct will allow for the determination of the function of MT invasion of spines and more broadly, to discern how MT-actin interactions affect cellular processes. Significance StatementO_LIThe LifeAct-MTED construct provides spatial and temporal control of microtubule depolymerization within individual cells C_LIO_LITargeting this construct directly to spines allows for the specific inhibition of microtubule dynamics into dendritic spines, without affecting microtubule dynamics in the dendritic shaft C_LIO_LIImplementation of the construct will allow for the testing of microtubule contributions to specific biological processes, without global disruption of microtubule dynamics C_LI

neuroscience↗

bioRxiv2019

Double UP: efficient in utero electroporation via internal controls

In Utero Electroporation is a powerful tool for testing the role of genes in neuronal migration, but this technique suffers from high degrees of variability due to multiple factors. Therefore, we developed Double UP, a novel approach that combines LoxP-flanked reporters and limiting Cre dosages to generate internal controls. This technique allows for more rigorous quantification of migration, while decreasing the number of animals, reagents and time to complete experiments.

neuroscience↗

bioRxiv2018

Challenges in estimating the impact of vaccination with sparse data

BackgroundThe synthetic control (SC) model is a powerful tool to quantify the population-level impact of vaccines, because it can adjust for trends unrelated to vaccination using a composite of control diseases. Because vaccine impact studies are often conducted using smaller subnational datasets, we evaluated the performance of SC models with sparse time series data. To obtain more robust estimates of vaccine effects from noisy time series, we proposed a possible alternative approach, \"STL+PCA\" method (seasonal-trend decomposition plus principal component analysis), which first extracts smoothed trends from the control time series and uses them to adjust the outcome.\n\nMethodsUsing both the SC and STL+PCA models, we estimated the impact of 10-valent pneumococcal conjugate vaccine (PCV10) on pneumonia hospitalizations among cases <12 months and 80+ years of age during 2004-2014 at the subnational level in Brazil. The performance of these models was also compared using simulation analyses.\n\nResultsThe SC model was able to adjust for trends unrelated to PCV10 in larger states but not in smaller states. The simulation analysis confirmed that the SC model failed to select an appropriate set of control diseases when the time series were sparse and noisy, thereby generating biased estimates of the impact of vaccination when secular trends were present. The STL+PCA approach decreased bias in the estimates for smaller populations.\n\nConclusionsEstimates from the SC model might be biased when data are sparse. The STL+PCA model provides more accurate evaluations of vaccine impact in smaller populations.

epidemiology↗