Biology subjects

McKnight, G. S.

Publications and source records attributed to McKnight, G. S..

3 recordsLinked to original sources

bioRxiv2022

Molecular and Anatomical Characterization of Parabrachial Neurons and Their Axonal Projections

The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are involved in behaviors including food and water intake, pain sensation, breathing regulation, as well as learning and responding appropriately to threatening stimuli. However, it is unclear how many PBN neuron populations exist and how different behaviors may be encoded by unique signaling molecules or receptors. Here we provide a repository of data on the molecular identity, spatial location, and projection patterns on dozens of PBN neuron subclusters. Using single-cell RNA sequencing, we identified 21 subclusters of neurons in the PBN and neighboring regions. Multiplexed in situ hybridization showed many of these subclusters are localized to distinct PBN subregions. We also describe two major ascending pathways that innervate distinct brain regions by analyzing axonal projections in 21 Cre-driver lines of mice. These results are all publicly available for download and provide a foundation for further interrogation of PBN functions and connections.

neuroscience↗

bioRxiv2021

Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing's syndrome

Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushings syndrome. Here we define mechanisms of action for the PKAc-L205R and W196R variants. Both Cushings mutants are excluded from A kinase anchoring protein (AKAP) signaling islands and consequently diffuse throughout the cell. Kinase-dead experiments show that PKA activity is required for cortisol hypersecretion. However, kinase activation is not sufficient, as only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate mutant PKAc into AKAP signaling islands abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Phosphoproteomics show that PKAc-L205R and W196R engage different mitogenic signaling pathways. ERK activity is elevated in adrenal-specific PKAc-W196R knock-in mice. Conversely, PKAc-L205R attenuates Hippo signaling, thereby upregulating the YAP/TAZ transcriptional co-activators. Thus, aberrant localization of each Cushings variant promotes the transmission of a distinct downstream pathogenic signal.

molecular biology↗

bioRxiv2020

Activation of Kiss1 neurons in the preoptic hypothalamus stimulates testosterone synthesis in adult male mice

Kisspeptin-expressing neurons in the rostral periventricular region of the third ventricle (RP3V) play an essential role in female reproduction. However, adult male mice were reported to have very few Kisspeptin-expressing neurons in the RP3V compared to females. This led to the hypothesis that Kiss1RP3V neurons are responsible for the ability of females, but not males, to generate a surge of LH, triggering ovulation and steroid synthesis in the female. Using mouse genetics and cell type-specific gene expression analysis, we show that male mice harbor almost as many Kiss1RP3V neurons as the female and that gene expression in these neurons is very similar. Specific activation of male Kiss1RP3V neurons expressing viral-encoded hM3Dq caused a surge in serum testosterone levels. These results demonstrate that Kiss1RP3V neurons are present in the adult male and fully capable of regulating the hypothalamic/pituitary/gonadal axis. We suggest that these neurons may continue to play a role in reproductive behavior in adult male mice.

neuroscience↗