Biology subjects

Goodrich, L.

Publications and source records attributed to Goodrich, L..

8 recordsLinked to original sources

bioRxiv2025

Modularity in the DCC extracellular domain elicits distinct effects on axon guidance

Complex neuronal circuits arise from a small set of cell-surface receptors that position neurons, promote axon extension, and define synaptic connections. A central receptor is Deleted in Colon Cancer (DCC), which mediates both short- and long-range axon guidance and confines migrating neurons to the central nervous system. DCCs versatility reflects its ability to interact at distinct sites of its extracellular domain with two ligands, Netrin-1 and Draxin, which also bind to each other. Alternative splicing further alters the Netrin-1 binding site and modulates affinity. By generating two mouse lines with mutations that selectively impair DCC binding to Netrin-1 and/or Draxin, we show that molecular modularity within the DCC extracellular domain is essential for precise circuit assembly. An eight-amino acid insertion in the DCClong isoform is required for Netrin-1-dependent long-range commissural axon guidance in the spinal cord. Conversely, isoleucine 372 in the Draxin binding site enables DCC clustering and is necessary for all known DCC functions, including axon guidance in the spinal cord and retina and neuronal migration in the brainstem. Draxin also supports long-range commissural guidance, but mutations in its binding site cause stronger defects. These results underscore how DCCs distinct modules drive specific developmental responses.

neuroscience↗

bioRxiv2025

Molecularly defined auditory neuron subtypes show different vulnerabilities to noise- and age-related synaptopathy in mice

Neuronal subtype-specific synaptopathy is a hallmark of many forms of neurodegeneration. We examined the cellular basis for synaptic vulnerability in the auditory system, where three subtypes of spiral ganglion neurons (SGNs)--Ia, Ib, and Ic--carry acoustic information from the cochlea to the brain. In response to noise and aging, a subset of synapses between inner hair cells and SGNs are lost, but it is unclear how this loss varies across SGN subtypes. Using genetic labelling, we showed that Ia SGNs have larger post-synaptic densities (PSDs) than Ib and Ic SGNs and are the most resilient subtype. Ia PSD volumes increased with age and were unchanged after noise exposure. By contrast, average Ib/Ic PSD volumes did not change with age but decreased with noise. Genetic reprogramming of Ib/Ic neurons to a Ia-like identity provided significant protection against noise-induced synaptopathy, linking identity to resilience and providing an entry point for therapeutics.

neuroscience↗

bioRxiv2024

Lateral olivocochlear neurons modulate cochlear responses to noise exposure

The sense of hearing originates in the cochlea, which detects sounds across dynamic sensory environments. Like other peripheral organs, the cochlea is subjected to environmental insults, including loud, damage-inducing sounds. In response to internal and external stimuli, the central nervous system directly modulates cochlear function through olivocochlear neurons (OCNs), which are located in the brainstem and innervate the cochlear sensory epithelium. One population of OCNs, the lateral olivocochlear (LOC) neurons, target spiral ganglion neurons (SGNs), the primary sensory neurons of the ear. LOCs alter their transmitter expression for days to weeks in response to noise exposure (NE), suggesting that they are well-positioned to tune SGN excitability over long time periods in response to auditory experience. To examine how LOCs affect auditory function after NE, we characterized the transcriptional profiles of OCNs and found that LOCs exhibit transient changes in gene expression after NE, including upregulation of multiple neuropeptide-encoding genes. Next, by generating intersectional mouse lines that selectively target LOCs, we chemogenetically ablated LOC neurons and assayed auditory responses at baseline and after NE. Compared to controls, mice lacking LOCs showed stronger NE-induced functional deficits one day later and had worse auditory function after a two-week recovery period. The number of remaining presynaptic puncta at the SGN synapse with inner hair cells did not differ between control and LOC-ablated animals, suggesting that the primary role of LOCs after NE is likely not one of protection, but one of compensation, ensuring that SGN function is enhanced during periods of need.

neuroscience↗

bioRxiv2023

High temporal frequency light response in mouse retina is mediated by ON and OFF bipolar cells and requires FAT3 signaling

Vision is initiated by the reception of light by photoreceptors and subsequent processing via downstream retinal neurons. Proper cellular organization depends on the multi-functional tissue polarity protein FAT3, which is required for amacrine cell connectivity and retinal lamination. Here we investigated the retinal function of Fat3 mutant mice and found decreases in physiological and perceptual responses to high frequency flashes. These defects did not correlate with abnormal amacrine cell wiring, pointing instead to a role in bipolar cell subtypes that also express FAT3. The role of FAT3 in the response to high temporal frequency flashes depends upon its ability to transduce an intracellular signal. Mechanistically, FAT3 binds to the synaptic protein PTP{sigma}, intracellularly, and is required to localize GRIK1 to OFF-cone bipolar cell synapses with cone photoreceptors. These findings expand the repertoire of FAT3s functions and reveal its importance in bipolar cells for high frequency light response.

neuroscience↗

bioRxiv2023

c-Maf and Mafb function combinatorially to establish SGN subtype-specific synaptic properties

Neurons develop diverse synapses that vary in content, morphology, and size. Although transcriptional regulators of neurotransmitter identity have been identified, it remains unclear how other synaptic features are patterned among neuronal subtypes. In the auditory system, glutamatergic synaptic properties vary across three subtypes of spiral ganglion neurons (SGNs) that collectively encode sound information. Here, we show that a combinatorial Maf transcription factor code establishes SGN subtype identity and shapes both shared and subtype-appropriate synaptic properties. We find that c-Maf and Mafb have independent and opposing effects on synaptic morphology and auditory function, while also acting redundantly to impart subtype identities and drive synaptic differentiation needed for normal auditory responses. Additionally, c-Maf and Mafb are expressed at different levels across subtypes and regulate subtype-appropriate gene expression in a dose-dependent manner. Thus, functional diversity of Maf family members enables flexible and robust control of gene expression needed to generate synaptic heterogeneity across neuronal subtypes.

neuroscience↗

bioRxiv2022

Experience-dependent flexibility in a molecularly diverse central-to-peripheral auditory feedback system

Brainstem olivocochlear neurons (OCNs) modulate the earliest stages of auditory processing through feedback projections to the cochlea and have been shown to influence hearing and protect the ear from sound-induced damage through unclear mechanisms. Here, we used single-nucleus sequencing, anatomical reconstructions, and electrophysiology to characterize OCNs during postnatal development and after sound exposure. We identified markers for known OCN subtypes, medial (MOC) and lateral (LOC) OCNs, and show that they express distinct cohorts of physiologically relevant genes that change over development. In addition, we discovered a neuropeptide-enriched LOC subtype that produces Neuropeptide Y along with other neurotransmitters. Throughout the cochlea, both LOC subtypes extend arborizations over wide frequency domains. Moreover, LOC neuropeptide expression is strongly upregulated days after acoustic trauma, potentially providing a sustained protective signal to the cochlea. OCNs are therefore poised to have diffuse, dynamic effects on early auditory processing over timescales ranging from milliseconds to days.

neuroscience↗

bioRxiv2021

Range contractions of the Broad-winged Hawk in the Northeast United States

The Broad-winged Hawk (BWHA, Buteo platypterus) is a small, secretive hawk with distinguishing broad black tail bands that breeds in northeastern North America. The hawk nests in deciduous or mixed forest, often near water, and close to clearings or forest edges. Land conversion and fragmentation alters the landscape and reduces the area of contiguous forest used by BWHA. This study seeks to determine the landscape characteristics influencing the apparent breeding range declines of the BWHA at the landscape scale. Landscape characteristics and BWHA presence data from 18,684 Breeding Bird Atlas blocks (each about 25km2) from Ohio, West Virginia, Maryland, Pennsylvania, and New York for two atlas period (1st Atlas: 1980s, 2nd Atlas: 2000s) were analyzed. Bayesian latent Gaussian models were fitted using INLA to determine best fit model for predicting the landscape characteristics associated with BWHA presence. The best models included landscape changes in land cover, including forest, water, urban, barren, farmland, and wetland and fragmentation of the landscape. Trends in loss were especially prevalent around the regions largest cities: New York, Philadelphia, Baltimore and Washington DC. Loss of BWHA at the block-level was associated with areas with less forest in the 2000s, a decline in size of largest forest patches, lower elevations and lower latitudes. We suggest that both habitat loss and climate change may be contributing to the range contraction of the Broad-winged Hawk in the northeast United States.

ecology↗

bioRxiv2019

Deep profiling reveals substantial heterogeneity of integration outcomes in CRISPR knock-in experiments

CRISPR/Cas technologies have transformed our ability to add functionality to the genome by knock-in of payload via homology-directed repair (HDR). However, a systematic and quantitative profiling of the knock-in integration landscape is still lacking. Here, we present a framework based on long-read sequencing and an integrated computational pipeline (knock-knock) to analyze knock-in repair outcomes across a wide range of experimental parameters. Our data uncover complex repair profiles, with perfect HDR often accounting for a minority of payload integration events, and reveal markedly distinct mis-integration patterns between cell-types or forms of HDR templates used. Our analysis demonstrates that the two sides of a given double-strand break can be repaired by separate pathways and identifies a major role for sequence micro-homology in driving donor mis-integration. Altogether, our comprehensive framework paves the way for investigating repair mechanisms, monitoring accuracy, and optimizing the precision of genome engineering.

genomics↗