Biology subjects

Ramanan, N.

Publications and source records attributed to Ramanan, N..

5 recordsLinked to original sources

bioRxiv2023

SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration

Reactive astrogliosis is a common pathological hallmark of central nervous system (CNS) injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These SrfGFAP-ERCKO astrocytes do not affect neuron survival, synapse numbers, synaptic plasticity or learning and memory. However, the brains of Srf knockout mice exhibited neuroprotection against kainic-acid induced excitotoxic cell death. Relevant to human neurodegenerative diseases, SrfGFAP-ERCKO astrocytes abrogate nigral dopaminergic neuron death and reduce {beta}-amyloid plaques in mouse models of Parkinsons and Alzheimers disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Zic3 enables bimodal regulation of tyrosine hydroxylase expression in dopaminergic neurons of olfactory bulb and midbrain

Dopaminergic (DA) neurons in the Olfactory bulb (OB) are involved in odor detection and discrimination. Transcription factor (TF) regulatory network responsible for their fate specification remains poorly understood and the spatial regulation of DA neurons remains elusive. In this study, mice exposed to odor stimulant exhibited specific upregulation of Zinc finger transcription factor of Cerebellum (ZIC) 3 along with Tyrosine Hydroxylase (TH). Stringent co-expression analysis showed ZIC3 and TH dual positive neurons in OB. Genetic manipulation showed ZIC3 to be both essential and sufficient to drive TH expression and essential for odor perception. ZIC3 interacts with ER81 and binds to region encompassing ER81 binding site in DA neurons and is indispensable for TH expression. In midbrain (MB), in the absence of ER81, ZIC3 switches its molecular partner and binds to Pitx3 promoter-a DA fate determinant. Under ectopic expression of ER81 in MB DA neurons, propensity of ZIC3 binding to Pitx3 promoter is compromised and its occupancy on Th promoter encompassing ER81 binding site is established, finally culminating in desired TH expression. Together, these findings reveal a unique ZIC3 mediated bimodal regulation of TH in OB and MB to ultimately facilitate DAergic fate.

neuroscience↗

bioRxiv2022

Prolactin-induced AMPK stabilizes alveologenesis and lactogenesis through regulation of STAT5 signaling

AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis at cellular and organismal levels. It has been shown to affect several steps of breast cancer progression in a context-dependent manner. However, its role in normal mammary gland development and physiology remains ill-explored. Here, we show that AMPK expression and activity increased within murine mammary epithelia from puberty to pregnancy with highest levels during lactation, and then declined during involution. In ex vivo cultures of mammary epithelial cells (MECs) in organotypic scaffolds, treatment with lactogenic hormone prolactin (PRL) enhanced AMPK expression and activity. To understand the role of AMPK on mammary morphogenesis in vivo, we generated mice with conditional knockout of AMPK isoforms 1 and 2 (AMPK KO) in MECs. AMPK KO mammary glands showed accelerated alveolar development with increased epithelial content of both luminal and myoepithelial lineages, suggestive of hyperproliferation. AMPK KO mice also showed elevated beta-casein expression during pregnancy and lactation. These observations were phenocopied upon treatment of ex vivo cultivated wild-type MECs with a cognate AMPK inhibitor. AMPK null MECs showed increased phosphorylated STAT5 which is known to drive alveologenesis downstream of prolactin signaling. Our study identifies a novel interplay between AMPK and PRL-STAT5 signaling that determines mammary alveologenesis and differentiation.

developmental biology↗

bioRxiv2020

Automated Morphometric Analysis Reveals Plasticity Induced by Chronic Antidepressant Treatment in Hippocampal Astrocytes

Nervous system development and plasticity involves changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyse the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by Principal Component Analysis. SMorph is tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.

neuroscience↗

bioRxiv2020

Vinculin mediated axon growth requires interaction with actin but not talin

Axon growth requires coordination of the actin cytoskeleton by actin-binding proteins in the extending neurites. Vinculin is a major constituent of focal adhesion but its role in neuronal migration and axon growth is poorly understood. We found that vinculin deletion in mouse neocortical neurons attenuated axon growth both in vitro and in vivo. Using different functional mutants of vinculin, we found that expression of a constitutively active vinculin significantly enhanced axon growth while the head-neck domain had a moderate inhibitory effect. Interesting, we found that vinculin-talin interaction was dispensable for axon growth and neuronal migration. Strikingly, expression of the tail domain delayed migration, increased branching and stunted axon. Inhibition of the Arp2/3 complex or abolishing the tail domain interaction with actin completely reversed the branching phenotype caused by tail domain expression without affecting axon length. Super-resolution microscopy showed increased mobile fraction of actin in tail domain expressing neurons. Our results provide novel insights into the role of vinculin and its functional domains in regulating neuronal migration and axon growth.

neuroscience↗