Biology subjects

Xu, P.-F.

Publications and source records attributed to Xu, P.-F..

3 recordsLinked to original sources

bioRxiv2023

Dissection of anterior mesendoderm segregation at single cell level in zebrafish

During gastrulation, the mesendoderm is firstly specified by morphogens such as Nodal, and then segregates into endoderm and mesoderm in a Nodal concentration-dependent manner. However, the mechanism underlying the segregation and crosstalk of different sub-groups within the meso- and endoderm lineages remains unclear. Here, taking zebrafish prechordal plate (PP) and anterior endoderm (Endo) as research model, using single-cell multi-omics and live imaging analyses, we show that anterior Endo progenitors originate directly from PP progenitors. A single-cell transcriptomic trajectory analysis of wild-type, ndr1 knockdown and lft1 knockout Nodal explants confirms the diversification of anterior Endo fate from PP progenitors. Gene Ontology (GO) enrichment analysis identifies that the change of chromatin organization potentiates the segregation of anterior endodermal cell fate from PP progenitors. Single-cell ATAC & RNA sequencing further reveals that two transcriptional regulators, gsc and ripply1, exhibit varied activation patterns in PP and anterior Endo cell trajectories at both the chromatin and RNA expression levels. We further demonstrate that Ripply1 functions coordinately with Gsc to repress anterior endodermal cell fate by directly binding to the cis-elements of sox32. Modulating the expression levels of these regulators tilts the cell fate decision between the PP and anterior Endo.

developmental biology↗

bioRxiv2023

The thalamic reticular nucleus-lateral habenula circuit regulates depressive-like behaviors in chronic stress and chronic pain

Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains elusive. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid pain in chronic stress is affected by this pathway. Together, our study demonstrates a novel sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.

neuroscience↗

bioRxiv2022

Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1

Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndromes pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells was highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was downregulated and amino acid metabolism was abnormal. Ribosomal profiling analysis showed decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Further, both L-leucine and Rheb, which can elevate translation via TOR pathway, rescued the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.

developmental biology↗