Biology subjects

Jeannotte, L.

Publications and source records attributed to Jeannotte, L..

3 recordsLinked to original sources

bioRxiv2025

A sustained Hox program delineates brainstem neurons essential for breathing

Respiratory neurons in the brainstem must diversify and acquire unique properties during development to enable breathing at birth. Dbx1-expressing progenitors give rise to functionally and molecularly distinct excitatory respiratory populations, including rhythm-generating pre-Botzinger complex (preBotC) neurons and phrenic motor neuron (MN)-projecting rostral Ventral Respiratory Group (rVRG) neurons. These neurons are organized rostrocaudally within the ventral respiratory column (VRC) but, despite their critical functions in breathing, the mechanisms that control their organization and diversification are not well understood. Here, we generate a novel genetic tool to label brainstem neurons within the VRC. We find that rVRG neurons selectively express Hox5 genes through postnatal stages. Selective deletion of all Hox5 paralogs from Dbx1-derived neurons leads to respiratory dysfunction, perinatal death, and changes in the pattern and amplitude of phrenic MN firing. We show that Hox5 inactivation leads to a caudal expansion of putative preBotC neurons, likely at the expense of the rVRG. Collectively, our findings indicate that Hox5 proteins are required for the delineation and functional specialization of excitatory brainstem neurons essential for breathing.

neuroscience↗

bioRxiv2024

Multimodal Hox5 activity generates motor neuron diversity

Motor neurons (MNs) are the final output of circuits driving fundamental behaviors, such as respiration and locomotion. Hox proteins are essential in generating the MN diversity required for accomplishing these functions, but the transcriptional mechanisms that enable Hox paralogs to assign distinct MN subtype identities despite their promiscuous DNA binding motif are not well understood. Here we show that Hoxa5 controls chromatin accessibility in all mouse spinal cervical MN subtypes and engages TALE co-factors to directly bind and regulate subtype-specific genes. We identify a paralog-specific interaction of Hoxa5 with the phrenic MN-specific transcription factor Scip and show that heterologous expression of Hoxa5 and Scip is sufficient to suppress limb-innervating MN identity. We also demonstrate that phrenic MN identity is stable after Hoxa5 downregulation and identify Klf proteins as potential regulators of phrenic MN maintenance. Our data identify multiple modes of Hoxa5 action that converge to induce and maintain MN identity.

developmental biology↗

bioRxiv2021

Elexacaftor/Tezacaftor/Ivacaftor alters branching morphogenesis of the mouse embryonic lung

IntroductionCFTR modulators triple combo-therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) has proven to clinically benefit homozygous and heterozygous F508del patients. As a result, an increasing number of pregnancies is expected. Studies of the potential impact of these modulators on the development of the foetus are mandatory. MaterialsWe used the early mouse embryonic lung organ culture model to analyse ex vivo the lung branching process and the relative expression of Fgf10, Fgfr2IIIb, Shh, and Hhip development regulator genes in different conditions: standard culture medium, treatment with ETI or with Forskolin {+/-} Inh172. Development of lung branching and distal bud caliber were evaluated in lung explants from heterozygous F508del Cftrtm1Eur/+ and control Cftrtm1Eur+/+ (WT) mouse embryos at E12.5 during pseudo-glandular stage. ResultsExposure to ETI of the Cftrtm1Eur/+ and WT lung explants induced a significant decrease in lung branching after 48h culture and the percentage of terminal bud dilations was significantly increased. These results were recapitulated by cAMP-dependent CFTR continuous activation by Forskolin and reversed by addition of Inh172. ETI induced a significant decrease in Fgf10, Fgfr2IIIb, Shh and Hhip expression in lung explants of both E12.5 Cftrtm1Eur/+ and WT embryos treated with ETI for 72h. ConclusionOur results provide evidence that the triple association Elexacaftor/Tezacaftor/Ivacaftor alters lung branching morphogenesis of WT and heterozygous F508del mouse embryos during the pseudo-glandular stage. Those results argue for a close monitoring of pregnancies in patients treated with these drugs. Plain LanguageO_ST_ABSIntroductionC_ST_ABSThe triple combo-therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) improves homozygous and heterozygous F508del patients. As a result, an increasing number of pregnancies is expected. Studies of this treatment on the development of the foetus are lacking. We incubated lungs of murine foetus not carrying CFTR mutation or F508del heterozygous. We show that ETI induces significant defect of lung development and the formation of cysts. These results are at least partly due to CFTR activation. Those results argue for a close monitoring of pregnancies in patients treated with these drugs.

pharmacology and toxicology↗