Biology subjects

Farooq, F.

Publications and source records attributed to Farooq, F..

3 recordsLinked to original sources

bioRxiv2026

ORMDL3-mediated SPT regulation Coordinates Myelin Sphingolipid and Protein Synthesis in Oligodendrocytes

Myelin is an essential and highly specialized membrane in the central and peripheral nervous systems that enwraps axons to accelerate electrical transmission and support neuronal health. The generation of this multilamellar structure requires a tightly coordinated synthesis of specific proteins and lipids. Among these are sphingolipids (SLs), which are major components of myelin. SL production is initiated by the serine palmitoyltransferase (SPT) enzyme complex, the rate-limiting enzyme in the de novo SL biosynthesis pathway. ORMDL proteins (ORMDL1-3) are the regulatory subunits of SPT, which, by sensing ceramide levels, tune SL flux. Although ORMDL3 has been linked to asthma and peripheral myelination, its role in CNS myelination and the CNS myelin-making oligodendrocytes (OLGs) remains unclear. We therefore assessed the function of ORMDL3 in OLs by generating a Cnp-Cre-driven, oligodendrocyte-specific Ormdl3 conditional knockout (cKO) mouse model. Loss of Ormdl3 selectively increased myelin SLs, particularly long-chain sulfatides, without altering ceramide or galactosylceramide abundance. These changes are most prominent around postnatal day 35, a developmental period of active myelin turnover. Ultrastructural analysis of optic nerves shows a thicker myelin sheath and increased axon caliber in cKO mice. Unexpectedly, deletion of Ormdl3 also increases levels of major myelin proteins (MBP, MOG, and PLP) and is accompanied by dynamic, region- and sex-dependent regulation of enzymes involved in sulfatide biosynthesis, without altering OLGs number or maturation. Together, for the first time, these findings identify Ormdl3 as a key regulator of SL homeostasis during developmental myelination and suggest that it helps synchronize lipid synthesis with myelin protein expression.

biochemistry↗

bioRxiv2026

Rewiring of the three-dimensional genome encodes regenerative potential in the adult central nervous system

The failure of adult central nervous system neurons to regenerate after injury has been attributed to transcriptional and epigenetic barriers, but whether three-dimensional genome organization constitutes an independent regulatory layer encoding regenerative potential remains unknown. Here we present the first genome-wide map of chromatin compartments, topologically associating domains, and loops across postnatal development, adult homeostasis, and spinal cord injury in the mouse motor cortex. Postnatal maturation progressively consolidates a growth-restrictive three-dimensional architecture, and spinal cord injury alone partially reverses this consolidation, re-engaging neonatal gene programs through reorganized but functionally recapitulative architecture despite minimal transcriptional activation. This reversion is directed rather than stochastic, preferentially targeting pro-growth gene networks, and reveals a latent three-dimensional memory of developmental growth states in the adult cortical genome. Strikingly, NR2F6, a transcription factor that promotes corticospinal axon regeneration, extends this reversion beyond the neonatal state toward an earlier embryonic chromatin configuration, a depth of developmental plasticity that injury alone cannot reach. These findings establish three-dimensional genome topology as a regulatory layer encoding regenerative potential in adult cortical neurons, demonstrating that successful CNS regeneration requires accessing embryonic rather than merely neonatal chromatin states, and reframing regenerative failure as a topological problem with new therapeutic targets.

neuroscience↗

bioRxiv2025

The individual isoforms of ORMDL, the regulatory subunit of serine palmitoyltransferase, have distinctive sensitivities to ceramide.

AbstractSphingolipids play crucial roles in cell membrane structure and in multiple signaling pathways. Sphingolipid de novo biosynthesis is mediated by the serine palmitoyltransferase (SPT) enzyme complex. Homeostatic regulation of this complex is dependent on its regulatory subunit, the ORMDLs, of which there are three isoforms. It is well established that the ORMDLs regulate SPT activity, but it is still unclear whether the three ORMDL isoforms have distinct functions and properties. Here, we focus on understanding the physiological importance of ORMDL isoforms (ORMDL1, ORMDL2, and ORMDL3) in regulating SPT activity and sphingolipid levels. This study delves into the differential responses of the SPT complexes containing different ORMDL isoforms to cellular ceramide levels. By using the CRISPR/Cas9 gene editing tool, we have developed Hela cell lines each of which harbor only one of the three ORMDL isoforms as well as a cell line deleted for all three isoforms. Consistent with other studies, we find that deletion of all three ORMDL isoforms desensitizes SPT to ceramide and dramatically increases levels of cellular sphingolipids. In contrast, each ORMDL isoform alone is capable of regulating SPT activity and maintaining normal levels of sphingolipid. Strikingly, however, we find that each ORMDL isoform exhibits isoform-specific sensitivity to ceramide. This suggests that the inclusion of specific ORMDL isoforms into the SPT complex may accomplish a fine-tuning of sphingolipid homeostasis. The study not only emphasizes the need for further investigation into the distinct roles of ORMDL isoforms but also sheds light on their potential as therapeutic targets. HighlightsO_LIRMDL isoforms detect varying ceramide levels to regulate SPT. C_LIO_LIHeLa cells, there is no compensation for the absence of the ORMDL isoform, neither at the total protein level nor at the mRNA level. C_LI

biochemistry↗