Biology subjects

Wagner, N. R.

Publications and source records attributed to Wagner, N. R..

3 recordsLinked to original sources

bioRxiv2022

Mating strategies in Caenorhabditis elegans populations are determined by male developmental history

Mating strategies, whether sexual or asexual, confer unique costs and benefits to populations and species that facilitate evolutionary processes. In wild isolates of Caenorhabditis elegans, mating strategies are dependent on developmental history. Outcrossing levels significantly increase when one or both parents have transiently passed through the stress-resistant dauer diapause stage. However, the molecular mechanisms of how life history alters mating strategies have not been systematically explored. Sex-specific responses to pheromones are a major driver of mating behaviors in C. elegans. We demonstrated previously that postdauer hermaphrodites exhibit a decreased avoidance of the pheromone ascr#3 due to the downregulation of the osm-9 TRPV channel gene in postdauer ADL neurons. Thus, we hypothesized that altered responses to pheromones in postdauer animals could contribute to increased outcrossing. We conducted mating assays using wild type N2 Bristol, as well as daf-3/co-SMAD and mut-16/Mutator strains that fail to downregulate osm-9 in postdauer hermaphrodite ADL neurons. First, we show that the outcrossing level of N2 Bristol correlated with the developmental history of males, and that postdauer males exhibited an increased ability to detect mates via pheromones compared to continuously developed males. In addition, DAF-3 plays a critical role in postdauer males to regulate mating, while playing a more minor role in hermaphrodites. Furthermore, the mut-16 strain exhibited negligible outcrossing, and attempts to rescue the outcrossing phenotype resulted in transgenerational sterility due to germline defects. Together, our results suggest a model whereby mating strategy is driven by developmental history under combinatorial control of TGF-{beta} and RNAi pathways.

genetics↗

bioRxiv2021

miR-409-3p represses Cited2 at the evolutionary emergence of the callosal and corticospinal projections

Callosal projection neurons are a broad population of interhemispheric projection neurons that extend an axon across the corpus callosum to connect the two cerebral hemispheres. The corticospinal tract, comprised of the axons of corticospinal projection neurons, is unique to mammals, and its full extension to the lumbar segments that control walking is, like the corpus callosum, unique to placental mammals. The emergence of these two distinct axonal tracts is thought to underpin the evolutionary expansion of complex motor and cognitive abilities. The molecular mechanisms regulating the divergence of corticospinal and callosal projection neurons are incompletely understood. Our recent work identifies a genomic cluster of microRNAs (12qF1/Mirg) unique to placental mammals. These clustered miRNAs are specifically expressed by corticospinal vs. callosal projection neurons during the molecular refinement of corticospinal vs. callosal projection neuron fate (1). One of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the callosal-expressed transcriptional regulator Lmo4. This conversion is partial, however, suggesting that miR-409-3p represses multiple callosal projection neuron control genes in order to specify corticospinal projection neurons. One potential additional target of miR-409-3p repression is the callosal-expressed transcriptional co-activator Cited2. Cited2 interacts genetically with Lmo4, and Lmo4 can partially functionally compensate for Cited2 in thymus development(2). Further, Cited2 and Lmo4 function as opposing molecular controls over specific areal identity within superficial layer callosal projection neurons of the somatosensory and motor cortices, respectively (3). Cited2 is highly expressed by callosal, relative to corticospinal, projection neurons from the earliest stages of neurogenesis. Cited2 is necessary for the expansion of intermediate progenitor cells (IPCs) in the subventricular zone (SVZ), and the resulting generation of superficial layer callosal projection neurons. Here we show that miR-409-3p and Cited2 interact in IPCs and in corticospinal vs. deep layer callosal projection neuron development. miR-409-3p represses the Cited2 3UTR in luciferase assays. Mirg, which encodes miR-409-3p, and Cited2, are reciprocally expressed in IPCs at e15.5 by qPCR. Furthermore, miR-409-3p gain-of-function results in a phenocopy of established Cited2 loss-of-function in IPCs. Later on, miR-409-3p and Cited2 exert opposing effects on the adoption of corticospinal vs. callosal projection neuron subtype identity. Taken together, our work suggests that miR-409-3p, and possibly other 12qF1 miRNAs, represses Cited2 in IPCs to limit their proliferation, and in developing corticospinal and deep layer callosal projection neurons to favor corticospinal fate.

neuroscience↗

bioRxiv2020

Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders

The mammalian neocortex develops from a single layer of neuroepithelial cells to form a six-layer heterogeneous mosaic of differentiated neurons and glial cells. This process requires a complex choreography of temporally and spatially restricted transcription factors and epigenetic regulators. Even subtle disruptions in this regulation can alter the way the neocortex forms and functions, leading to a neurodevelopmental disorder. One epigenetic regulator that is essential for the precise development of the neocortex is CITED2 (CBP/p300 Interacting Transactivator with ED-rich termini). Cited2 is highly expressed by intermediate progenitor cells in the subventricular zone during the generation of the superficial layers of the neocortex. A forebrain-specific conditional knockout of Cited2 (cKO) exhibits reduced proliferation of intermediate progenitor cells embryonically, leading to reduced thickness of the superficial layers and a specific reduction in the somatosensory neocortical length postnatally. Further, the Cited2 cKO displays decreased corpus callosum volume and dysregulation of precise neuronal connectivity within the somatosensory cortex. Here, we explore the behavioral consequences resulting from this aberrant neocortical development. We demonstrate that Cited2 cKO mice display decreased maternal separation-induced ultrasonic vocalizations as neonates, and an increase in the repetitive behavior of rearing and lack of habituation following repeated acoustic startle as adults. They do not display alterations in anxiety-like behavior, overall locomotor activity or social interactions. Together with the morphological, molecular, and connectivity disruptions, these results identify the Cited2 cKO neocortex as an ideal system to study mechanisms underlying neurodevelopmental and neuroanatomical disruptions with relevance to human neurodevelopmental disorders.

neuroscience↗