Biomedical subjects

Shanthini Sockanathan

Publications and source records attributed to Shanthini Sockanathan.

7 recordsLinked to original sources

PubMed2006

Mesodermal and neuronal retinoids regulate the induction and maintenance of limb innervating spinal motor neurons.

During embryonic development, the generation, diversification and maintenance of spinal motor neurons depend upon extrinsic signals that are tightly regulated. Retinoic acid (RA) is necessary for specifying the fates of forelimb-innervating motor neurons of the Lateral Motor Column (LMC), and the specification of LMC neurons into medial and lateral subtypes. Previous studies implicate motor neurons as the relevant source of RA for specifying lateral LMC fates at forelimb levels. However, at the time of LMC diversification, a significant amount of retinoids in the spinal cord originates from the adjacent paraxial mesoderm. Here we employ mouse genetics to show that RA derived from the paraxial mesoderm is required for lateral LMC induction at forelimb and hindlimb levels, demonstrating that mesodermally synthesized RA functions as a second source of signals to specify lateral LMC identity. Furthermore, reduced RA levels in postmitotic motor neurons result in a decrease of medial and lateral LMC neurons, and abnormal axonal projections in the limb; invoking additional roles for neuronally synthesized RA in motor neuron maintenance and survival. These findings suggest that during embryogenesis, mesodermal and neuronal retinoids act coordinately to establish and maintain appropriate cohorts of spinal motor neurons that innervate target muscles in the limb.

Aldehyde Oxidoreductases↗

PubMed2005

Dorsal-ventral patterning: a view from the top.

The generation of dorsal interneurons in the spinal cord is dependent upon specific signaling pathways and the subsequent establishment of progenitor domains mediated by cross-repressive interactions of different groups of transcription factors. These events lead to the implementation of specific differentiation programs that direct the development of distinct dorsal interneuron subtypes. Recent studies have taken advantage of complementary gain and loss-of-function studies in the chick and mouse to clarify the in vivo roles of transforming growth factor beta signaling, basic helix-loop-helix and homeodomain transcription factors in dorsal interneuron development. The challenge now lies in identifying the precise molecular mechanisms involved and applying these insights to understanding how more ventrally located dorsal interneurons are specified.

Animals↗

PubMed2005

Transmembrane protein GDE2 induces motor neuron differentiation in vivo.

During neural development, coordinate regulation of cell-cycle exit and differentiation is essential for cell-fate specification, cell survival, and proper wiring of neuronal circuits. However, the molecules that direct these events remain poorly defined. In the developing spinal cord, the differentiation of motor neuron progenitors into postmitotic motor neurons is regulated by retinoid signaling. Here, we identify a retinoid-inducible gene, GDE2 (glycerophosphodiester phosphodiesterase 2), encoding a six-transmembrane protein that is necessary and sufficient to drive spinal motor neuron differentiation in vivo. A single amino acid mutation in the extracellular catalytic domain abolishes protein function. This reveals a critical role for glycerophosphodiester metabolism in motor neuron differentiation.

Amino Acid Sequence↗

PubMed2005

Molecular mechanisms of RNAi: implications for development and disease.

Research over the past few years has led to dramatic new discoveries on the role of double-stranded RNA (dsRNA) in the cell. RNA duplexes have been shown to orchestrate epigenetic changes, repress translation, and direct mRNA degradation in a sequence-specific manner. These diverse effects of dsRNA on gene expression have been termed RNA interference (RNAi). In addition to playing a role in viral defense and silencing transposons, RNAi also has a critical function in a number of developmental processes in the embryo. In this review, we explore these roles and discuss the molecular mechanisms behind dsRNA-mediated gene silencing. Further, we address the use of RNAi as a tool to study gene function in biology, and as a strategy for treating human disease.

Animals↗

PubMed2003

A requirement for retinoic acid-mediated transcriptional activation in ventral neural patterning and motor neuron specification.

The specification of neuronal fates in the ventral spinal cord depends on the regulation of homeodomain (HD) and basic-helix-loop-helix (bHLH) proteins by Sonic hedgehog (Shh). Most of these transcription factors function as repressors, leaving unresolved the link between inductive signaling pathways and transcriptional activators involved in ventral neuronal specification. We show here that retinoid signaling and the activator functions of retinoid receptors are required to pattern the expression of HD and bHLH proteins and to specify motor neuron identity. We also show that fibroblast growth factors (FGFs) repress progenitor HD protein expression, implying that evasion of FGF signaling and exposure to retinoid and Shh signals are obligate steps in the emergence of ventral neural pattern. Moreover, joint exposure of neural progenitors to retinoids and FGFs suffices to induce motor neuron differentiation in a Shh-independent manner.

Aldehyde Oxidoreductases↗

PubMed2003

Retinoid receptor signaling in postmitotic motor neurons regulates rostrocaudal positional identity and axonal projection pattern.

The identity of motor neurons diverges markedly at different rostrocaudal levels of the spinal cord, but the signals that specify their fate remain poorly defined. We show that retinoid receptor activation in newly generated spinal motor neurons has a crucial role in specifying motor neuron columnar subtypes. Blockade of retinoid receptor signaling in brachial motor neurons inhibits lateral motor column differentiation and converts many of these neurons to thoracic columnar subtypes. Conversely, expression of a constitutively active retinoid receptor derivative impairs the differentiation of thoracic motor neuron columnar subtypes. These findings provide evidence for a regionally restricted role for retinoid signaling in the postmitotic specification of motor neuron columnar identity.

Animals↗

PubMed2003

Towards cracking the code: LIM protein complexes in the spinal cord.

Combinatorial transcription codes are used widely in the developing nervous system to specify the development of many distinct cell types. Although this strategy maximizes the use of small numbers of proteins, the molecular basis for imposing specificity remains unclear. A recent study has addressed this question by demonstrating that the favoring of hexameric complexes of specific LIM homeodomain proteins over tetramers could dictate the choice between motor neuron versus interneuron fate.

Animals↗