Sex, Age, and Hunger Regulate Behavioral Prioritization through Dynamic Modulation of Chemoreceptor Expression
Current BiologyDA Ryan, RM Miller, KH Lee, S Neal, K Fagan, P Sengupta and DS Portman
2014
Adaptive behavioral prioritization requires flexible outputs from fixed neural circuits. In C. elegans, the prioritization of feeding versus mate searching depends on biological sex (males will abandon food to search for mates, whereas hermaphrodites will not) as well as developmental stage and feeding status. Previously, we found that males are less attracted than hermaphrodites to the food-associated odorant diacetyl, suggesting that sensory modulation may contribute to behavioral prioritization.
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Multiple doublesex-Related Genes Specify Critical Cell Fates in a C. elegans Male Neural Circuit
PLoS ONESiehr MS, Koo PK, Sherlekar AL, Bian X, Bunkers MR, Miller RM, Portman DS, Lints R.
2011
In most animal species, males and females exhibit differences in behavior and morphology that relate to their respective roles in reproduction. DM (Doublesex/MAB-3) domain transcription factors are phylogenetically conserved regulators of sexual development. They are thought to establish sexual traits by sex-specifically modifying the activity of general developmental programs. However, there are few examples where the details of these interactions are known, particularly in the nervous system.
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The Wnt/β-Catenin Asymmetry Pathway Patterns the Atonal Ortholog lin-32 to Diversify Cell Fate in a Caenorhabditis elegans Sensory Lineage
Journal of NeuroscienceRenee M. Miller and Douglas S. Portman
2011
Each sensory ray of the Caenorhabditis elegans male tail comprises three distinct neuroglial cell types. These three cells descend from a single progenitor, the ray precursor cell, through several rounds of asymmetric division called the ray sublineage. Ray development requires the conserved atonal-family bHLH gene lin-32, which specifies the ray neuroblast and promotes the differentiation of its progeny. However, the mechanisms that allocate specific cell fates among these progeny are unknown. Here we show that the distribution of LIN-32 during the ray sublineage is markedly asymmetric, localizing to anterior daughter cells in two successive cell divisions. The anterior–posterior patterning of LIN-32 expression and of differentiated ray neuroglial fates is brought about by the Wnt/β-catenin asymmetry pathway, including the Wnt ligand LIN-44, its receptor LIN-17, and downstream components LIT-1 (NLK), SYS-1 (β-catenin), and POP-1 (TCF). LIN-32 asymmetry itself has an important role in patterning ray cell fates, because the failure to silence lin-32 expression in posterior cells disrupts development of this branch of the ray sublineage. Together, our results illustrate a mechanism whereby the regulated function of a proneural-class gene in a single neural lineage can both specify a neural precursor and actively pattern the fates of its progeny. Moreover, they reveal a central role for the Wnt/β-catenin asymmetry pathway in patterning neural and glial fates in a simple sensory lineage.
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PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.
Science Translational MedicineZheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR
2010
Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson's disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention.
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Specific a- and b-tubulin isotypes optimize the functions of sensory cilia in Caenorhabditis elegans
GeneticsHurd DD, Miller RM, Núñez L, Portman DS
2010
Primary cilia have essential roles in transducing signals in eukaryotes. At their core is the ciliary axoneme, a microtubule-based structure that defines cilium morphology and provides a substrate for intraflagellar transport. However, the extent to which axonemal microtubules are specialized for sensory cilium function is unknown. In the nematode Caenorhabditis elegans, primary cilia are present at the dendritic ends of most sensory neurons, where they provide a specialized environment for the transduction of particular stimuli. Here, we find that three tubulin isotypes--the alpha-tubulins TBA-6 and TBA-9 and the beta-tubulin TBB-4--are specifically expressed in overlapping sets of C. elegans sensory neurons and localize to the sensory cilia of these cells. Although cilia still form in mutants lacking tba-6, tba-9, and tbb-4, ciliary function is often compromised: these mutants exhibit a variety of sensory deficits as well as the mislocalization of signaling components. In at least one case, that of the CEM cephalic sensory neurons, cilium architecture is disrupted in mutants lacking specific ciliary tubulins. While there is likely to be some functional redundancy among C. elegans tubulin genes, our results indicate that specific tubulins optimize the functional properties of C. elegans sensory cilia.
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