Biology subjects

Phillips, K.

Publications and source records attributed to Phillips, K..

4 recordsLinked to original sources

bioRxiv2025

Multi-omic analysis of the ciliogenic transcription factor RFX3 reveals a role in promoting activity-dependent responses via enhancing CREB binding in human neurons

Heterozygous loss-of-function (LoF) variants in RFX3, a transcription factor known to play key roles in ciliogenesis, result in autism spectrum disorder (ASD) and neurodevelopmental delay. RFX binding motifs are also enriched upstream of genes found to be commonly dysregulated in transcriptomic analyses of brain tissue from individuals with idiopathic ASD. Still, the precise functions of RFX3 in the human brain is unknown. Here, we studied the impact of RFX3 deficiency using human iPSC-derived neurons and forebrain organoids. Biallelic loss of RFX3 disrupted ciliary gene expression and delayed neuronal differentiation, while monoallelic loss of RFX3 did not. Instead, transcriptomic and DNA binding analyses demonstrated that monoallelic RFX3 loss disrupted synaptic target gene expression and diminished neuronal activity-dependent gene expression. RFX3 binding sites co-localized with CREB binding sites near activity-dependent genes, and RFX3 deficiency led to decreased CREB binding and impaired induction of CREB targets in response to neuronal depolarization. This study demonstrates a novel role of the ASD-associated gene RFX3 in shaping neuronal synaptic development and plasticity.

neuroscience↗

bioRxiv2024

Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner

Genetic variants can alter the profile of heritable molecules such as small RNAs in sperm and oocytes, and in this manner ancestral genetic variants can have a significant effect on offspring phenotypes even if they are not inherited. Here we show that wild type female mice descended from ancestors with a mutation in the mammalian germ cell gene Khdc3 have hepatic metabolic defects that persist over multiple generations. We find that genetically wild type females descended from Khdc3 mutants have transcriptional dysregulation of critical hepatic metabolic genes, which persist over multiple generations and pass through both female and male lineages. This was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with mutational ancestry. The oocytes of Khdc3-null females, as well as their wild type descendants, had dysregulation of multiple small RNAs, suggesting that these epigenetic changes in the gametes transmit the phenotype between generations. Furthermore, injection of serum from wild type mice with ancestral history of Khdc3 mutation into wild type females is sufficient to cause hepatic transcriptional dysregulation in their offspring. Our results demonstrate that ancestral mutation in Khdc3 can produce transgenerational inherited phenotypes, potentially indefinitely.

genetics↗

bioRxiv2021

The dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after major surgery

Major surgery and critical illness produce a potentially life threatening systemic inflammatory response. The hypothalamic-pituitary-adrenal (HPA) axis is one of the key physiological systems that counterbalances this systemic inflammation through changes in adrenocorticotrophic hormone (ACTH) and cortisol. These hormones normally exhibit highly correlated ultradian pulsatility with an amplitude modulated by circadian processes. However, these dynamics are disrupted by major surgery and critical illness. In this work, we characterise the inflammatory, ACTH and cortisol responses of patients undergoing cardiac surgery and show that the HPA axis response can be classified into one of three phenotypes: single-pulse, two-pulses and multiple-pulses dynamics. We develop a mathematical model of cortisol secretion and metabolism that predicts the physiological mechanisms responsible for these different phenotypes. We show that the effects of inflammatory mediators are important only in the single-pulse pattern in which normal pulsatility is lost - suggesting that this phenotype could be indicative of the greatest inflammatory response. Investigating whether and how these phenotypes are correlated with clinical outcomes will be critical to patient prognosis and designing interventions to improve recovery.

physiology↗

bioRxiv2019

Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071

Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and to impairments in gait and balance, and the resulting risks for falls, in patients with Parkinsons disease (PD). Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. Here we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that an M1 PAM amplifies such transient signaling, thereby enhancing and rescuing attentional performance. Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period assessing their capacity for recovering performance. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance recovery. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose). Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, and also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d) in lesioned rats and facilitated the adoption of a more liberal response bias (B\"D) in all female rats. Collectively, these findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.

neuroscience↗