Biology subjects

Carroll, P.

Publications and source records attributed to Carroll, P..

8 recordsLinked to original sources

bioRxiv2025

Functional Equivalence of the Proneural Genes Neurog1 and Neurog2 in the Developing Dorsal Root Ganglia Highlights the Importance of Timing of Neurogenesis in Biasing Somatosensory Precursor Fates

Distinct subfamilies of proneural bHLH transcription factors (TFs) control neurogenesis and influence neuronal fate specification throughout the developing nervous system. While members of different subfamilies generally display divergent expression and functions, those within the same subfamily are often co-expressed, raising questions about their respective roles. Here, we assess the functional equivalence of the two paralogous proneural TFs Neurog1 and Neurog2, focusing on neurons of the dorsal root ganglia (DRG) which underlie our ability to process somatosensory information. During development, distinct classes of DRG neurons -classified as mechano/proprioceptors or thermo/nociceptors-are generated during two successive neurogenic phases, which are respectively controlled by Neurog2 and Neurog1, in line with their dynamic and complementary spatiotemporal expression patterns. Therefore, in this system, each TF appears to play unique roles in regulating neurogenesis and specifying distinct neuronal identities. Yet, using a gene replacement strategy in vivo, we show that, despite subtle divergences masked by dose-compensation effects, Neurog1 and Neurog2 are essentially functionally interchangeable in all aspects of DRG development, indicating that their apparent functional discrepancies primarily stem from divergent evolution of their gene regulatory regions, rather than of their respective biochemical properties. Notably, we definitively establish that neither TF directly specifies specific somatosensory neuron identities. This result, combined with : (i) a new series of birth-dating experiments supporting that most mechano/proprioceptive and thermo/nociceptive subtypes are predominantly born during successive time-windows; and (ii) analyses of complementary transgenic mouse models in which opposite temporal shifts of neurogenesis -either delayed onset or premature arrest-have predictable opposite impacts on their DRG content, highlight that the fate choice of somatosensory precursors toward the mechano/proprioceptive or thermo/nociceptive lineages critically depends on the timing of their birth.

developmental biology↗

bioRxiv2023

FLT3 signaling inhibition preserves opioid analgesia while abrogating tolerance and hyperalgesia

Opioid analgesia is counteracted on chronic use by tolerance and hyperalgesia inducing dose escalation and life-threatening overdoses. Mu opiate receptors (MOR) expressed in primary sensory neurons were recently found to control tolerance and hyperalgesia, but the underlying mechanisms remained elusive. Here we show that genetic inactivation of fms-like tyrosine kinase receptor 3 (FLT3) receptor in sensory neurons abrogates morphine tolerance and hyperalgesia by preventing MOR-induced hyperactivation of the cAMP signaling pathway and subsequent excitatory adaptive processes. Moreover, the specific FLT3 inhibitor BDT001 potentiates morphine analgesia in acute and chronic pain models, without aggravating morphine adverse effects, and reverses tolerance and hyperalgesia once installed. Thus, FLT3 appears as a key regulator of the MOR signaling pathway and its pharmacological blockade shows promise to enhance chronic opioid analgesic efficacy.

neuroscience↗

bioRxiv2022

Touch receptor end-organ innervation and function requires sensory expression of the transcription factor Meis2.

Touch sensation is primarily encoded by mechanoreceptors, called Low-Threshold Mechanoreceptors (LTMRs), with their cell bodies in the Dorsal Root Ganglia (DRG). Because of their great diversity in terms of molecular signature, terminal endings morphology and electrophysiological properties, mirroring the complexity of tactile experience, LTMRs are a model of choice to study the molecular cues differentially controlling neuronal diversification. While the transcriptional codes that define different LTMR subtypes have been extensively studied, the molecular players that participate in their late maturation and in particular in the striking diversity of their end-organ morphological specialization are largely unknown. Here we identified the TALE homeodomain transcription factor Meis2 as a key regulator of LTMRs target-field innervation. Meis2 is specifically expressed in cutaneous LTMRs and its expression depends on target-derived signals. While LTMRs lacking Meis2 survived and are normally specified, their end-organ innervations, electrophysiological properties and transcriptome are differentially and markedly affected, resulting in impaired sensory-evoked behavioral responses. These data establish Meis2 as a major transcriptional regulator controlling the orderly formation of sensory neurons innervating peripheral end-organs required for light touch.

developmental biology↗

bioRxiv2021

Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia

Background & AimsThe c-Myc (Myc) bHLH-ZIP transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation and proliferation. This "Myc Network" cross-talks with the "Mlx Network", which consists of the Myc-like proteins MondoA and ChREBP and Max-like Mlx. Together, this "Extended Myc Network" regulates both common and distinct genes targets. Here we studied the consequence of Myc and/or Mlx ablation in the liver, particularly those pertaining to hepatocyte proliferation, metabolism and spontaneous tumorigenesis. MethodsWe examined the ability of hepatocytes lacking Mlx (MlxKO) or Myc+Mlx (double KO or DKO) to repopulate the liver over an extended period of time in a murine model of Type I tyrosinemia. We also compared this and other relevant behaviors, phenotypes and transcriptomes of the livers to those from previously characterized MycKO, ChrebpKO and MycKO x ChrebpKO mice. ResultsHepatocyte regenerative potential deteriorated as the Extended Myc Network was progressively dismantled. Genes and pathways dysregulated in MlxKO and DKO hepatocytes included those pertaining to translation, mitochondrial function and non-alcoholic fatty liver disease (NAFLD). The Myc and Mlx Networks were shown to cross-talk, with the latter playing a disproportionate role in target gene regulation. All cohorts also developed NAFLD and molecular evidence of early steatohepatitis. Finally, MlxKO and DKO mice displayed extensive hepatic adenomatosis. ConclusionsIn addition to demonstrating cooperation between the Myc and Mlx Networks, this study revealed the latter to be more important in maintaining proliferative, metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis. SynopsisThe Myc and Mlx Networks exhibit extensive cross-talk and regulate distinct but overlapping sets of transcriptional targets. The current work demonstrates the cooperation between these two Networks in supporting the regenerative capabilities of normal hepatocytes while also revealing that the Mlx Network serves as a suppressor of spontaneous hepatic adenomatosis

cancer biology↗

bioRxiv2020

MLX balances metabolism and stress to suppress apoptosis and maintain spermatogenesis

Male germ cell production is a metabolically-driven and apoptosis-prone process. Here we show that the glucose-sensing transcription factor MLX, and its binding partner MondoA, are both required for male fertility in the mouse, as well as survival of human tumor cells derived from the male germ line. Loss of Mlx results in altered metabolism as well as activation of multiple stress pathways and germ cell apoptosis in the testes. This is concomitant with dysregulation of the expression of male-specific germ cell transcripts and proteins, manifesting as oligoasthenoteratozoospermia (OAT). Our genomic and functional analyses identify loci directly bound by MLX involved in these processes, including metabolic targets, apoptotic effectors and obligate components of male-specific germ cell development. These in vivo and in vitro studies implicate MLX and other members of the proximal MYC network, such as MNT, in regulation of metabolism and differentiation, as well as in suppression of intrinsic and extrinsic death signaling pathways in both spermatogenesis and male germ cell tumors. Highlights- The MAX-like bHLHLZ protein MLX is required for male fertility, but not embryonic development. - MLX and its heterodimeric partner MondoA are each required for both male fertility and survival of male germ cell tumors. - Genomic analysis identifies direct MLX targets associated with metabolism, stress and male germ cell development. - Loss of MLX alters MYC network genome occupancy and transcriptional output.

developmental biology↗

bioRxiv2018

A GABAergic Maf-expressing interneuron subset regulates the speed of locomotion in Drosophila

Interneurons (INs) coordinate motoneurons activity to generate adequate patterns of muscle contractions, providing animals with the ability to adjust their body posture and to move over a range of speeds. In the Drosophila larvae several IN subtypes have been morphologically described and their function well documented. However, the general lack of molecular characterization of those INs prevents the identification of evolutionary counterparts in other model animals, limiting our understanding of widespread principles ruling neuronal circuits organization and functioning. Here we characterize a highly restricted neuronal subset expressing the Maf transcription factor Traffic Jam (TJ). We found that TJ+ neurons are highly diverse and their activation using intersectional genetics disrupted larval body posture and locomotion speed. We also showed that a small subset of TJ+ GABAergic INs, singled out by the unique expression of Per, Fkh, Grain and Hlh3b, a molecular signature reminiscent to V2b INs in vertebrate, impacted the larvae crawling speed.

neuroscience↗

bioRxiv2018

Optimization of the DsRed fluorescent protein for use in Mycobacterium tuberculosis

ABSTRACTO_ST_ABSObjectiveC_ST_ABSWe have previously codon-optimized a number of red fluorescent proteins for use in Mycobacterium tuberculosis (mCherry, tdTomato, Turbo-635). We aimed to expand this repertoire to include DsRed, another widely used and flexible red fluorescent protein.\n\nResultsWe generated expression constructs with a full length DsRed under the control of one of three strong, constitutive promoters (Phsp60, PrpsA or PG13) for use in mycobacteria. We confirmed that full length DsRed (225 amino acids) was expressed and fluoresced brightly. In contrast to mCherry, truncated versions of DsRed lacking several amino acids at the N-terminus were not functional. Thus, we have expanded the repertoire of optimized fluorescent proteins for mycobacteria.

molecular biology↗

bioRxiv2017

The MYC antagonist MNT autoregulates its expression and supports proliferation in MAX deficient cells

MNT is a transcription factor of the MXD family. MNT-MAX dimers down-regulate genes by binding to E-box sequences, which can also be bound by MYC-MAX to activate transcription. MNT has been described as a modulator of MYC activity but little is known about MNT regulation and whether MNT has MAX-independent functions. Using a MAX deficient cell line and siRNA-mediated silencing of MAX, we show that in the absence of MAX, the total MNT levels are elevated and that MNT localizes both in the cytoplasm and the nucleus. In contrast, MNT is predominantly nuclear when MAX is expressed. MNT is required for optimal cell proliferation even in the absence of MAX, being the first report of a MAX-independent function of MNT. Interestingly, MNT forms homodimers and autoregulates its expression by repressing its own promoter. The tight MNT regulation and its activity in absence of MAX suggest its importance on cell homeostasis.

cancer biology↗