Biology subjects

Sen, J.

Publications and source records attributed to Sen, J..

7 recordsLinked to original sources

bioRxiv2026

Spatial transcriptomics reveals BMP-dependent stage-specific transcriptional programs underlying migration of cortical neurons

The laminar architecture of the mammalian neocortex depends on precise radial migration of newborn neurons to the appropriate cortical layers. This process is governed by the integration of extracellular signals with cell-intrinsic transcriptional programs. BMP signaling has been previously demonstrated to be essential for radial migration of late-born (E15.5) upper-layer cortical neurons. However, the gene expression programs downstream of BMP signaling that regulate this process remained unknown. To address this, we combined temporally targeted in utero electroporation with GeoMx Digital Spatial Profiling (DSP) to map BMP-responsive transcriptional programs in E15.5-born layer II/III neurons at two defined developmental timepoints: E17.5, when neurons actively migrate through the intermediate zone, and postnatal day 0 (P0), when they have completed migration and have attained their laminar position. BMP inhibition produced largely non-overlapping transcriptional changes at these two stages. At E17.5, chromatin-regulatory programs and ribosomal protein gene expression were collectively upregulated upon BMP inhibition. However, by P0, the same cohort of ribosomal genes exhibited downregulation while membrane lipid biosynthesis and synaptic specialization pathways became dominant, revealing a stage-dependent transcriptional switch. A subset of shared BMP-responsive genes was regulated in opposite directions at these two stages, which lent further support to the hypothesis that there is a temporal reorganization of BMP-dependent transcriptional outputs. We selected four candidates from among the BMP-responsive genes for functional studies, namely Mfap4, Olfm2, Adora1, and Arpp21, which belong to diverse functional categories, including extracellular matrix proteins, G protein-coupled receptors, secreted glycoproteins, and RNA-binding proteins. RNAi-mediated knockdown of all four candidates resulted in radial migration defects that closely phenocopied inhibition of BMP signaling, establishing these genes as functional effectors of the BMP signaling pathway regulating neuronal migration.

developmental biology↗

bioRxiv2025

Cdh-2 modulates tissue stiffness and cortical F-actin distribution in neuroepithelial cells to drive forebrain roof plate invagination.

The invagination of the dorsal forebrain roof plate is critical for cerebral hemisphere formation. Although mutations in several genes have been linked to holoprosencephaly (HPE), and studies in chick embryos have implicated key signaling pathways, the mechanisms by which mechanical forces drive roof plate invagination remain poorly understood. To address this gap, we employed atomic force microscopy to map the spatiotemporal changes in tissue stiffness across the dorsal forebrain in the chick embryo during roof plate invagination. Our analysis revealed that neuroepithelium that is uniformly stiff initially, undergoes dramatic remodelling during this period of morphological change. Ultimately a pronounced stiffness gradient emerges, with the roof plate midline becoming markedly more compliant than the dorsolateral regions. Through expression screening, we identified Cdh2 as a candidate molecular regulator, whose spatiotemporal expression pattern closely mirrors the observed stiffness gradient. Mechanistically, we found that the interplay between Cdh2 and F-actin modulates tissue stiffness by regulating Cdh2 expression levels, apical adherens junction stability, and cortical F-actin distribution along the apico-basal axis of neuroepithelial cells. These findings underscore the importance of apico-basal localization of Cdh2 and provide critical insights into the mechanical forces and molecular interactions that govern forebrain roof plate morphogenesis, while also shedding light on the pathogenesis of HPE.

developmental biology↗

bioRxiv2025

IP6K1 interacts with the syndecan SDC4 to support secretory granule biogenesis in gastric chief cells

Inositol hexakisphosphate kinases (IP6Ks) catalyse the synthesis of the inositol pyrophosphate 5-InsP7, and regulate diverse physiological processes. Mice lacking IP6K1 display reduced body weight despite normal food intake, a phenotype that is more apparent in juvenile mice during their rapid growth phase. Additionally, Ip6k1-/- mice exhibit decreased serum albumin, elevated faecal protein, and reduced skeletal muscle mass compared to Ip6k1+/+ mice, suggestive of a deficiency in protein digestion in the absence of IP6K1. We found that IP6K1 is expressed throughout the mouse gastrointestinal tract, and is especially enriched in the cytoplasm of chief cells in the stomach, which are responsible for the storage and secretion of digestive enzymes. Pepsinogen C (PGC) containing granules were sparse, and gastric lipase F (LIPF) granules were completely absent in the gastric glands of Ip6k1-/- mice, despite normal expression levels of these enzymes, implicating IP6K1 in digestive enzyme granule biogenesis. Consequently, the level of the active protease pepsin C was decreased in the gastric lumen of Ip6k1-/- mice compared with their wild type counterparts. CRISPR/Cas9-mediated deletion of IP6K1 in the gastric adenocarcinoma cell line AGS was able to recapitulate the phenotype of reduced PGC granule intensity seen in gastric chief cells of Ip6k1-/- mice. PGC granule formation was restored in IP6K1-/- AGS cells by the reintroduction of catalytically active or inactive IP6K1, indicating that IP6K1 supports the formation of secretory granules independent of its ability to synthesise 5-InsP7. The proteoglycan SDC4, identified as an interactor of IP6K1, was seen to co-localise and co-migrate with PGC granules in IP6K1+/+ but not in IP6K1-/- AGS cells. Our findings identify IP6K1 as a novel regulator of secretory granule biogenesis in gastric chief cells, to influence protein digestion in the mammalian stomach.

physiology↗

bioRxiv2023

Inositol hexakisphosphate kinase 1 is essential for cell junction integrity in the mouse seminiferous epithelium

Inositol hexakisphosphate kinases (IP6Ks) are enzymes that catalyse the synthesis of the inositol pyrophosphate 5-IP7 which is involved in the regulation of many physiological processes in mammals. The IP6K paralog IP6K1 is expressed at high levels in the mammalian testis, and its deletion leads to sterility in male mice. Here, we show that the loss of IP6K1 in mice causes a delay in the first wave of spermatogenesis. Testes from juvenile Ip6k1 knockout mice show downregulation of transcripts that are involved in cell adhesion and formation of the testis-specific inter-Sertoli cell impermeable junction complex known as the blood-testis barrier (BTB). We demonstrate that loss of IP6K1 in the mouse testis causes BTB disruption associated with transcriptional misregulation of the tight junction protein claudin 3, and subcellular mislocalization of the gap junction protein connexin 43. In addition to BTB disruption, we also observe loss of germ cell adhesion in the seminiferous epithelium of Ip6k1 knockout mice, ultimately resulting in premature sloughing of round spermatids into the epididymis. Mechanistically, we show that loss of IP6K1 in the testis enhances cofilin activity due to increased AKT/ERK and integrin signalling, resulting in destabilization of the actin-based cytoskeleton in Sertoli cells and germ cell loss.

cell biology↗

bioRxiv2023

Epigenetic signature of human immune aging: the GESTALT study.

Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood borne immune cell types (naive B, naive CD4+and CD8+ T cells, granulocytes, monocytes and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousand of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In-silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1{beta}) and REST transcription factor motifs respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to transcription factor motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.

molecular biology↗

bioRxiv2020

MicroRNA-19b regulates proliferation and differentiation along the medial-lateral axis of the developing avian pallium

Unlike the six-layered organization of neurons in the mammalian neocortex, the avian pallium features spatially-segregated neuronal clusters with partially conserved gene expression. While efforts to uncover similarities between the avian pallium and mammalian neocortex have persisted, the mechanisms of pallial development in birds have not been comprehensively explored. Here, we have established the role of a highly conserved microRNA, miR-19b, in controlling proliferation in the embryonic avian forebrain, by regulating the expression of E2f8, a cell-cycle inhibitor and NeuroD1, a neuronal differentiation factor. Further, investigation revealed that there exists a proliferation-dependent specification of pallial neurons in birds, similar to that in mammals. In summary, these findings suggest a profound role of miR-19b in shaping the avian pallium and indicate a closer resemblance of developmental mechanisms between the avian pallium and the mammalian neocortex.

developmental biology↗

bioRxiv2017

BMP signalling is critical for maintaining homeostasis of hair follicles and intestine in adult mice

BMP signalling play critical roles during embryonic development, however, its roles have not been extensively studied in the maintenance of adult tissue homeostasis. In this study we have used temporal knock out of Bmp2 and Bmp4 to uncover the role of BMP signalling in adult mice. We observed rapid changes in the adult hair follicles and the intestine within two days of depleting BMP signalling, which demonstrates the critical and acute requirement of BMP signalling in maintaining homeostasis in these tissues. In addition, our study demonstrates that while BMP signalling is required for maintenance of quiescence in telogen hair follicles, it is needed for survival and proliferation in late anagen hair follicles. Our study also reveals differential requirement of BMP signalling in differentiation of distinct intestinal cell types. In addition, Loss of BMP signalling rapidly promotes early neoplastic transformations in mouse intestine.

developmental biology↗