Biology subjects

Bianco, A. C.

Publications and source records attributed to Bianco, A. C..

7 recordsLinked to original sources

bioRxiv2025

Thyroid hormone promotes fetal neurogenesis

Maternal low thyroxine (T4) serum levels during the first trimester of pregnancy correlate with cerebral cortex volume and mental development of the progeny, but why neural cells during early fetal brain development are vulnerable to maternal T4 levels remains unknown. In this study, using iPSCs obtained from a boy with a loss-of-function mutation in MCT8--a transporter previously identified as critical for thyroid hormone uptake and action in neural cells--we demonstrate that thyroid hormones induce transcriptional changes that promote the progression of human neural precursor cells along the dorsal projection trajectory. Consistent with these findings, single-cell, spatial, and bulk transcriptomics from MCT8-deficient cerebral organoids and cultures of human neural precursor cells underscore the necessity for optimal thyroid hormone levels for these cells to differentiate into neurons. The controlled intracellular activation of T4 signaling occurs through the transient expression of the enzyme type 2 deiodinase, which converts T4 into its active form, T3, alongside the coordinated expression of thyroid hormone nuclear receptors. The intracellular activation of T4 in NPCs results in transcriptional changes important for their division mode and cell cycle progression. Thus, T4 is essential for fetal neurogenesis, highlighting the importance of adequate treatment for mothers with hypothyroidism.

neuroscience↗

bioRxiv2025

Overnutrition directly impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations

Thyroid hormones (THs: T3 and T4) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) to energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt--but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for novel obesity therapies that tackle hypothyroidism--which are much-needed, as no current obesity treatment works for everyone.

physiology↗

bioRxiv2022

A PATHWAY FOR T3 SIGNALING IN THE BRAIN TO IMPROVE THE VARIABLE EFFECTIVENESS OF THERAPY WITH L-T4

The effectiveness of therapy for hypothyroidism with levothyroxine (L-T4) depends on patients ability to activate T4 to T3 --altered in carriers of a common deiodinase polymorphism (Thr92Ala-DIO2). Some patients that exhibit impaired mood and cognition improve with liothyronine (L-T3), but the underlying mechanisms remain unknown. Here we show that the T3-indicator mouse carrying the Thr92Ala-DIO2 polymorphism exhibits a hippocampal-specific reduction in T3 activation and signaling that limits the effectiveness of L-T4 therapy. To understand the L-T3 effect, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering relatively large amounts of T3 to the cell nucleus, doubling the expression of the T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and the type 3 deiodinase (Dio3), which transports and inactivates T3, respectively. Notwithstanding, T3 gets away from degradation because D3 active center is in the cytosol. These findings provide (i) a basis for the variable effectiveness of L-T4 therapy, (ii) a pathway for L-T3 to reach neurons, and (iii) resolve the paradox of T3 signaling in the brain amid high D3 activity.

neuroscience↗

bioRxiv2022

Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus

Soluble urokinase-type plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. Here we report the presence of C-terminal suPAR fragment, D2D3, in patients with diabetic nephropathy. D2D3-positive human sera inhibited glucose-stimulated insulin release in human islets and were associated with patients requiring insulin therapy. D2D3 transgenic mice presented kidney disease and diabetes marked by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic {beta}-cell mass, and high fasting glucose. D2D3 fragment dysregulated glucose-induced cytoskeletal dynamics, impaired maturation and trafficking of insulin granules, and inhibited bioenergetics of {beta}-cells in culture. An anti-uPAR antibody restored {beta}-cell function in D2D3 transgenic mice. We show that the D2D3 fragment injures the kidney and pancreas, offering a unique dual therapeutic approach for kidney diseases and insulin-dependent diabetes. SummaryProteolytic suPAR fragment, D2D3, simultaneously injures two organs, the kidney and pancreas, thus causing a dual organ disease.

physiology↗

bioRxiv2020

NEONATAL THYROXINE ACTIVATION MODIFIES EPIGENETIC PROGRAMMING OF THE LIVER

In the neonatal liver, a peak of type 2 deiodinase (D2) activity accelerates local T3 production and the expression of thyroid hormone (TH)-responsive genes. Here we show that this acute increase in T3 signaling permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increased H3K9me3 levels during post-natal days 1-5 (P1-P5) in discrete chromatin areas, and methylation of 1,508 DNA sites (H-sites) that remained in the adult mouse liver. These sites were associated with 1,551 areas of reduced chromatin accessibility (RCA; Atac-seq) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,525 genes (RNA-seq). There was strong correlation between H-sites and RCA sites (r=0.85; p<0.0002), suggesting a cause-effect relationship. The analysis of chromosome conformation capture (Hi-C) data revealed a set of 57 repressed genes that have a promoter RCA in close contact with an intergenic RCA ~300 Kbp apart, including Foxa2 that plays an important role during development. Thus, the post-natal surge in hepatic D2 activity and TH-signaling prevents discrete DNA methylation and modifies the transcriptome of the adult mouse. This explains how the systemic T3 hormone acts locally during development to define future chromatin accessibility and expression of critically relevant hepatic genes.

physiology↗

bioRxiv2020

The transcriptional repressor Zfp125 modifies hepatic energy metabolism in response to fasting and insulin resistance

Zfp125 is a transcriptional repressor that inhibits hepatic VLDL secretion. Here we show that mice with liver-specific Zfp125 knockdown exhibited lower respiratory quotient, reduced glycemia and pyruvate-stimulated liver glucose output, and higher levels of {beta}-hydroxyl-butyrate. Microarray and ChIP-seq studies identified Zfp125 peaks in the promoter of 135 metabolically relevant genes, including genes involved in fatty acid oxidation and ketogenesis, e.g. Ppara, Cpt1a, Bdh1 and Hmgcs2. Repression by Zfp125 involved recruitment of the corepressors Kap1 and the histone methyl transferase Setdb1, increasing the levels of H3K9me3, a heterochromatin marker of gene silencing. The resulting increase in acetyl-CoA levels accelerated gluconeogenesis through allosteric activation of pyruvate carboxylase. Zfp125 knockdown in isolated mouse hepatocytes amplified the induction of ketogenesis by glucagon or insulin resistance, whereas the expression of key gluconeogenic genes Pck1 and G6pc was amplified by Zfp125. These findings place Zfp125 at the center of fuel dysregulation of type 2 diabetes.

physiology↗

bioRxiv2019

Accelerating functional gene discovery in osteoarthritis

Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

genetics↗