Cirqueira, C. S. | Search bioRxiv

bioRxiv2024

Temporal Analysis of Pituitary Transcriptional Dynamics in Mice Models of Hypopituitarism During Postnatal Development

Congenital hypopituitarism is characterized by deficient pituitary hormone production, affecting growth and development. The molecular mechanisms underlying pituitary development and dysfunction in hypopituitarism remain incompletely understood. We investigated the expression of key pituitary development markers in three mouse models of congenital hypopituitarism, with molecular alterations in the Prop1, Pou1f1, and GSU genes across critical postnatal developmental stages: neonatal (P0), early postnatal (P7), pubertal (4 weeks), and adult (8 weeks). We assessed mRNA and protein levels of the pituitary stem cell markers (SOX2), proliferation marker (Ki67) and pituitary hormones, correlating these with pituitary function and disease. Prop1 deficiency led to significant upregulation of Sox2 and Hesx1 during early postnatal development and in adulthood, diverging from the relatively stable expression patterns observed in Pou1f1 and GSU mutants. Despite some variations, overall Sox2 and Ki67 expression profiles were similar between Prop1 and Pou1f1 mutants. Prop1 mutants exhibited altered pituitary morphology, with increased SOX2-positive cells suggesting disrupted stem cell migration. During the pubertal period, a subset of hormone-producing cells in Prop1 mutants co-expressed SOX2, indicating differentiation without restoring normal pituitary function. Hormone analysis revealed transient gonadotropin production and secretion during sexual maturation in Prop1 mutants, without recovery of the hypogonadal phenotype. Our study elucidates the complex transcriptional dynamics of pituitary development markers in mouse models of congenital hypopituitarism, highlighting the pivotal role of Prop1 in regulating stem cell marker expression. The distinct transcriptional responses in Prop1 mutants during key developmental windows shed light on the mechanisms of pituitary dysgenesis and the persistent inability to fully recover pituitary function, despite transient hormonal changes during puberty. These insights contribute to a better understanding of pituitary development and dysfunction in congenital hypopituitarism.

developmental biology↗

bioRxiv2019

Genomic Surveillance of Yellow Fever Virus Epidemic Waves in Sao Paulo, Brazil, 2017 - 2018

Sao Paulo (SP), a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in SP, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in SP, we generated and analysed virus genomic data and epizootic case data from NHP in SP. We report the occurrence of three spatiotemporally distinct phases of the outbreak in SP prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in SP, mostly sampled from non-human primates between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in Sao Paulo state at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern Sao Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of SP state. Our results shed light on the sylvatic transmission of yellow fever in highly fragmented forested regions in SP state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species. Authors SummarySince July 2016, the southeast region of Brazil has experienced the largest yellow fever virus (YFV) outbreak in decades. Sao Paulo is the most densely populated state in southeast Brazil. The outbreak has caused serious public health concern in the state, as YFV does not normally circulate widely there and most of the 21 million inhabitants were correspondingly unvaccinated against YFV when the outbreak began. In Brazil, YFV typically circulates among non-human primates, and human cases represent isolated spillover events from this predominantly sylvatic cycle. Understanding the epidemiological dynamics and spread of YFV in non-human primates is therefore critical for contextualising human cases, and guiding vaccination strategies that can better protect local human populations. Here, we aim to contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in SP. We analyse the geographic and temporal distribution of observed cases of YFV in non-human primates in Sao Paulo state, and identify three distinct phases of the epizootic. We generate sequence data from 51 YFV-positive cases and perform phylogenetic and phylogeographic analyses aimed at understanding the spatial spread of YFV in Sao Paulo state. Analyses of these data indicate that YFV spread from the north of Sao Paulo state into more densely populated southern regions. Although we observe substantial heterogeneity in the rate at which different sampled YFV lineages spread, the typical rate of spread was low with a mean rate of ~1 km per day. This is consistent with a scenario in which the majority of transmission events occurred between non-human primates and sylvatic vectors across forested patches. Article Summary LineGenomic surveillance of yellow fever in Sao Paulo during the 2016-2018 epizootic

epidemiology↗