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Keller, J.

Publications and source records attributed to Keller, J..

At least 37 records · Page 2Linked to original sources

Conservation of an immune homeostasis module in land plants

Calcium-dependent protein kinases (CDPKs) decode cellular calcium transients and play diverse roles in plant growth and stress responses, including immunity. In Arabidopsis thaliana (At, Arabidopsis thereafter), AtCPK28 contributes to immune homeostasis by phosphorylating subgroup IV plant U-box proteins AtPUB22/24/25/26, which target the key immune receptor-like cytoplasmic kinase (RLCK) AtBIK1 for turnover. While this module is conserved in multiple angiosperms, it is unclear if the role of CPK28 in immune homeostasis is conserved more broadly across land plants. Here, we took an evolutionary comparative approach to understand the role of CPK28. We identified a single CPK28 ortholog in the liverwort Marchantia polymorpha, MpCPK28, which exhibits Ca2+-dependent kinase activity that is inhibited by calmodulin in vitro. We identified the subgroup IV plant U-box protein MpPUB20e as a substrate of MpCPK28. MpPUB20e is able to ubiquitinate MpPBLa, the functional ortholog of AtBIK1. We also provide preliminary evidence that MpPBLa undergoes proteasomal degradation in Marchantia, suggesting that optimization of MpPBLa protein accumulation is conserved across land plants. Interestingly, while loss of CPK28 function in multiple angiosperm species results in enhanced immune signaling, we find that Marchantia Mpcpk28 mutant alleles do not display enhanced immune-triggered production of reactive oxygen species or resistance to two pathogens. However, transgenic expression of MpCPK28 was able to restore function in Arabidopsis cpk28-1 mutants, suggesting latent functional conservation of MpCPK28. Furthermore, while AtCPK28-mediated phosphorylation of Thr95/94 on AtPUB25/26 is known to contribute to their activation, we could not observe a functional role for the equivalent residue Thr122 on MpPUB20e. Taken together, our results suggest that post-translational fine-tuning by CPK28 is likely to have refined the PUB-BIK1 module in the vascular plant lineages.

plant biology↗

The molecular mechanism of on-demand sterol biosynthesis at organelle contact sites

Contact-sites are specialized zones of proximity between two organelles, essential for organelle communication and coordination. The formation of contacts between the Endoplasmic Reticulum (ER), and other organelles, relies on a unique membrane environment enriched in sterols. However, how these sterol-rich domains are formed and maintained had not been understood. We found that the yeast membrane protein Yet3, the homolog of human BAP31, is localized to multiple ER contact sites. We show that Yet3 interacts with all the enzymes of the post-squalene ergosterol biosynthesis pathway and recruits them to create sterol-rich domains. Increasing sterol levels at ER contacts causes its depletion from the plasma membrane leading to a compensatory reaction and altered cell metabolism. Our data shows that Yet3 provides on-demand sterols at contacts thus shaping organellar structure and function. A molecular understanding of this proteins functions gives new insights into the role of BAP31 in development and pathology.

cell biology↗

Conservation of symbiotic signalling across 450 million years of plant evolution

HighlightO_LIThe common symbiotic pathway is activated during arbuscular mycorrhizal symbiosis in Marchantia paleacea C_LIO_LIThe three core members of the common symbiotic pathway are essential for symbiosis in Marchantia paleacea C_LIO_LIThe molecular function of the CCaMK/CYCLOPS module is conserved across land plants C_LIO_LISymbiotic signalling has been conserved in plants for 450 million years C_LI The colonization of land by plants 450 million years ago revolutionized life on Earth1. The fossil record2 and genetic evidence in extant species3 suggest that this transition was facilitated by interactions with symbiotic arbuscular mycorrhizal (AM) fungi4. This ancestral symbiosis relied on the biosynthesis of chemicals by the host plant, both as signals5 and as nutrients3. In angiosperms, a signalling pathway involving the receptor-like kinase SYMRK/DMI26,7, the Calcium and Calmodulin-dependent protein kinase CCaMK/DMI38 and the transcription factor CYCLOPS/IPD39,10 has been described as the common symbiosis pathway (CSP), essential for the establishment of the AM symbiosis and the root-nodule symbiosis11. Phylogenetic and comparative phylogenomic analyses indicated an ancient origin of the CSP, present in all extant land plants forming intracellular symbioses12-15. Trans-complementation assays of the angiosperm mutants with orthologs from diverse species further indicated the conservation of the molecular function of the CSP across the embryophytes9,12,14-16. However, this correlative evidence did not allow testing the ancestral biological function of the CSP. In this study we demonstrate that SYMRK, CCaMK and CYCLOPS are essential for the colonization by AM fungi in bryophytes, indicating that plants have maintained a dedicated signalling pathway to support symbiotic interactions for 450 million years.

plant biology↗

Annexin and calcium-regulated priming of legume root cells for endosymbiotic infection

Legumes establish endosymbioses with arbuscular mycorrhizal (AM) fungi or rhizobia bacteria to improve mineral nutrition. Symbionts are hosted in privileged habitats, root cortex (for AM fungi) or nodules (for rhizobia) for efficient nutrient exchange. To reach these habitats, plants form cytoplasmic bridges, which are key to predicting and guiding the cellular route of entry of fungal hyphae or rhizobia-filled infection threads (ITs). However, the underlying mechanisms are poorly studied. Here we show that unique ultrastructural changes and Ca2+ spiking signatures, closely linked to MtAnn1 annexin accumulation, accompany rhizobia-associated bridge formation. Loss of MtAnn1 function in M. truncatula affects Ca2+ spike amplitude, cytoplasmic configuration and rhizobia infection efficiency, consistent with a role of MtAnn1 in regulating infection priming. MtAnn1, which evolved in species establishing intracellular symbioses, is also AM-symbiosis-induced and required for proper arbuscule formation. Together, we propose that MtAnn1 is part of an ancient Ca2+-regulatory module for transcellular endosymbiotic infection.

plant biology↗

The Marchantia pangenome reveals ancient mechanisms of plant adaptation to the environment

Plant adaptation to a terrestrial life 450 million years ago played a major role in the evolution of life on Earth. This shift from an aquatic environment has been mostly studied by focusing on flowering plants. Here, we gathered a collection of 133 accessions of the non-vascular plants Marchantia polymorpha and studied its intraspecific diversity using selection signature analyses, genome-environment association study and a gene-centered pangenome. We identified adaptive features shared with flowering plants, such as peroxidases or nucleotide-binding and leucine-rich repeat (NLR), which likely played a role in the adaptation of the first land plants to the terrestrial habitat. The M. polymorpha pangenome also harbored lineage-specific accessory genes absent from seed plants. We conclude that different land plants lineages still share many elements from the genetic toolkit evolved by their most recent common ancestor to adapt to the terrestrial habitat, refined by lineage specific polymorphisms and gene family evolutions.

plant biology↗

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization

Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/548550v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@cea57corg.highwire.dtl.DTLVardef@d29642org.highwire.dtl.DTLVardef@186ea5aorg.highwire.dtl.DTLVardef@83eaae_HPS_FORMAT_FIGEXP M_FIG Artwork was created in BioRender. C_FIG

cell biology↗

Chromosome-level genomes of multicellular algal sisters to land plants illuminate signaling network evolution

The filamentous and unicellular algae of the class Zygnematophyceae are the closest algal relatives of land plants. Inferring the properties of the last common ancestor shared by these algae and land plants allows us to identify decisive traits that enabled the conquest of land by plants. We sequenced four genomes of filamentous Zygnematophyceae (three strains of Zygnema circumcarinatum and one strain of Z. cylindricum) and generated chromosome-scale assemblies for all strains of the emerging model system Z. circumcarinatum. Comparative genomic analyses reveal expanded genes for signaling cascades, environmental response, and intracellular trafficking that we associate with multicellularity. Gene family analyses suggest that Zygnematophyceae share all the major enzymes with land plants for cell wall polysaccharide synthesis, degradation, and modifications; most of the enzymes for cell wall innovations, especially for polysaccharide backbone synthesis, were gained more than 700 million years ago. In Zygnematophyceae, these enzyme families expanded, forming co-expressed modules. Transcriptomic profiling of over 19 growth conditions combined with co-expression network analyses uncover cohorts of genes that unite environmental signaling with multicellular developmental programs. Our data shed light on a molecular chassis that balances environmental response and growth modulation across more than 600 million years of streptophyte evolution. HIGHLIGHTSO_LIGenomes of four filamentous algae (Zygnema) sisters to land plants C_LIO_LIZygnema are rich in genes for multicellular growth and environmental acclimation: signaling, lipid modification, and transport C_LIO_LICell wall innovations: diversification of hexameric rosette cellulose synthase in Zygnematophyceae C_LIO_LICo-expression networks reveal conserved modules for balancing growth and acclimation C_LI

evolutionary biology↗

Reinforcement Learning Is Impaired in the Sub-acute Post-stroke Period

BackgroundNeurorehabilitation approaches are frequently predicated on motor learning principles. However, much is left to be understood of how different kinds of motor learning are affected by stroke causing hemiparesis. Here we asked if two kinds of motor learning often employed in rehabilitation, (1) reinforcement learning and (2) error-based adaptation, are altered at different times after stroke. MethodsIn a cross-sectional design, we compared learning in two groups of patients with stroke, matched for their baseline motor execution deficit on the paretic side. The early group was tested within 3 months following stroke (N = 35) and the late group was tested more than 6 months after stroke (N = 30). Two types of task were studied: one based on reinforcement learning and the other on error-based learning. ResultsWe found that reinforcement learning was impaired in the early but not the late group, whereas error-based learning was unaffected compared to controls. These findings could not be attributed to differences in baseline execution, cognitive impairment, gender, age, or lesion volume and location. ConclusionsThe presence of a specific impairment in reinforcement learning in the first 3 months after stroke has important implications for rehabilitation. It might be necessary to either increase the amount of reinforcement feedback given early or even delay onset of certain forms of rehabilitation training, e.g., like constraint-induced movement therapy, and instead emphasize others forms of motor learning in this early time period. A deeper understanding of stroke-related changes in motor learning capacity has the potential to facilitate the development of new, more precise treatment interventions.

neuroscience↗

SCN1A-deficient hiPSC-derived excitatory neuronal networks display mutation-specific phenotypes

Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioral problems and developmental delay. 80% of Dravet syndrome patients have a mutation in SCN1A, encoding NaV1.1. Milder clinical phenotypes, such as GEFS+ (generalized epilepsy with febrile seizures plus), can also arise from SCN1A mutations. Predicting the clinical phenotypic outcome based on the type of mutation remains challenging, even when the same mutation is inherited within one family. Both this clinical and genetic heterogeneity add to the difficulties of predicting disease progression and tailored prescription of anti-seizure medication. A better understanding of the neuropathology of different SCN1A mutations, might give insight in differentiating the expected clinical phenotype and best fit treatment choice. Initially it was recognized that loss of Na+ -current in inhibitory neurons specifically resulted in disinhibition and consequently seizure generation. However, the extent to which excitatory neurons contribute to the pathophysiology is currently debated, and might depend on the patient clinical phenotype or the specific mutation in SCN1A. To examine the genotype-phenotype correlations of SCN1A mutations in relation to excitatory neurons, we investigated a panel of patient-derived excitatory neuronal networks differentiated on multi-electrode arrays. We included patients with different clinical phenotypes, harboring different mutations in SCN1A, plus a family where the same mutation leads to both GEFS+ and Dravet syndrome. We hitherto describe a previously unidentified functional excitatory neuronal network phenotype in the context of epilepsy, which corresponded to seizurogenic network prediction patterns elicited by proconvulsive compounds. We find that excitatory neuronal networks were differently affected, dependent on the type of SCN1A mutation, but not on clinical severity. Specifically, pore domain mutations could be distinguished from voltage sensing domain mutations. Furthermore, all patients showed aggravated neuronal network responses upon febrile temperatures. While the basal neuronal network phenotypes could not be distinguished based on patient clinical severity, retrospective drug screening revealed that anti-seizure medication only affected GEFS+ patient-, but not Dravet patient-derived neuronal networks in a patient specific and clinically relevant manner. In conclusion, our results indicate a mutation-specific excitatory neuronal network phenotype, which recapitulates the foremost clinically relevant features, providing future opportunities for precision therapies. HighlightsO_LIHuman stem cell derived excitatory neurons are affected by mutations in SCN1A and display mutation-specific, but not clinical phenotype specific, neuronal network phenotypes C_LIO_LIThe neuronal network phenotype we describe corresponds to seizurogenic network prediction patterns in vitro C_LIO_LIExcitatory neuronal networks respond to Dravet syndrome clinically relevant triggers, like febrile temperatures and Dravet-contraindicated ASM Carbamazepine C_LIO_LIRetrospective drug screening revealed that GEFS+ neuronal networks, but not Dravet neuronal networks respond to ASM in a patient-specific and clinical relevant manner C_LI

neuroscience↗

Comparative phylotranscriptomics reveals a 110 million years-old symbiotic program

Symbiotic interactions have structured past and present ecosystems and shaped the evolution of life. As any trait, the symbiotic state observed in extant species builds on ancestral and conserved features, and lineage-specific innovations. From these mixed origins, defining the ancestral state of symbiotic associations is challenging although it is instrumental for understanding how symbiotic abilities emerge from non-symbiotic states. Here we aimed at reconstructing the intermediate steps leading to the root-nodule nitrogen-fixing symbiosis (RNS) observed in some extant flowering plants. For this, we compared the transcriptomic responses of nine host plants in response to symbiotic bacteria. We included the mimosoid legume Mimosa pudica for which we assembled a chromosome-level genome and generated the transcriptomic response to experimentally evolved bacterial symbionts. With this dataset, we reconstructed the ancestral RNS transcriptome, composed of most already described symbiotic genes together with hundreds of novel candidates. We found that the response to the chemical signals produced by the symbiont, nodule organogenesis and nitrogen-fixation are predominantly linked to ancestral responses, although these traits have diversified in the different nitrogen-fixing lineages. We detected a clear signature of recent and convergent evolution for the ability to release intracellular symbiosomes in two legume lineages, exemplified by the expression of different classes of small proteins in each group, potentially leading to the convergent gain of symbiotic evolutionary stability. Our findings demonstrate that most of the novelties for RNS were mostly in place in the most recent common ancestor of the RNS-forming species that lived on Earth 110 million years ago. Graphical abstractA little graphical/nice phylogeny with nodes of interest HighlightsO_LIWe sequenced a high-quality genome of the Mimosoideae Mimosa pudica C_LIO_LIThe nitrogen-fixing root-nodule symbiosis relies on an ancestral transcriptomic response C_LIO_LIAll symbiotic traits involve genes of the ancestral symbiotic program C_LIO_LISymbiont perception, nodule organogenesis and nitrogen-fixation are essentially ancestral processes C_LIO_LIConvergent evolution of intracellular accommodation of symbionts additionally involves lineage-specific genes C_LI

plant biology↗

A novel cis-element enabled bacterial uptake by plant cells

The root nodule symbiosis (RNS) of plants with nitrogen-fixing bacteria is phylogenetically restricted to a single clade of flowering plants, which calls for yet unidentified trait acquisitions and genetic changes in the last common ancestor. Here we discovered - within the promoter of the transcription factor gene Nodule Inception (NIN) - a cis-regulatory element (PACE), exclusively present in members of this clade. PACE was essential for restoring infection threads (ITs) in nin mutants of the legume Lotus japonicus. PACE sequence variants from RNS-competent species appeared functionally equivalent. Evolutionary loss or mutation of PACE is associated with loss of this symbiosis. During early stages of nodule development, PACE dictates gene expression in a spatially restricted domain containing cortical cells carrying ITs. Consistent with its expression domain, PACE-driven NIN expression restored the formation of cortical ITs, also when engineered into the NIN promoter of tomato. Our data pinpoint PACE as a key evolutionary invention that connected NIN to a pre-existing symbiosis signal transduction cascade that governs the intracellular accommodation of arbuscular mycorrhiza fungi and is conserved throughout land plants. This connection enabled bacterial uptake into plant cells via intracellular support structures like ITs, a unique and unifying feature of this symbiosis.

plant biology↗

Remorin proteins serve as membrane topology scaffolds in plants

Organization of membrane topologies in plants has so far been mainly attributed to the cell wall and the cytoskeleton. Taking rhizobial infections of legume root cells, where plasma membranes undergo dynamic and large-scale topology changes, as an initial model, we challenged this paradigm and tested whether additional scaffolds such as plant-specific remorins that accumulate on highly curved and often wall-less plasma membrane domains, control local membrane dynamics. Indeed, loss-of-function mutants of the remorin protein SYMREM1 failed to develop stabilized membrane tubes as found in colonized cells in wild-type plants, but released empty membrane spheres instead. Expression of this and other remorins in wall-less protoplasts allowed engineering different membrane topologies ranging from membrane blebs to long membrane tubes. Reciprocally, mechanically induced membrane indentations were equally stabilized by SYMREM1. This function is likely supported by remorin oligomerization into antiparallel dimers and the formation of higher order membrane scaffolding structures. Taken together we describe an evolutionary confined mechanism that allows the stabilization of large-scale membrane conformations and curvatures in plants. One-sentence summaryThe remorin SYMREM1 evolved as structural membrane scaffold that stabilizes membrane tubulation and curvature during symbiotic intracellular infections.

plant biology↗

Phylogenomics reveals the evolutionary origin of lichenization in chlorophyte algae

Mutualistic symbioses have contributed to major transitions in the evolution of life. Here, we investigate the evolutionary history and the molecular innovations at the origin of lichens, which are a symbiosis established between fungi and green algae or cyanobacteria. We de novo sequence the genomes or transcriptomes of 12 lichen algal symbiont (LAS) and closely related non-symbiotic algae (NSA) to improve the genomic coverage of Chlorophyte algae. We then perform ancestral state reconstruction and comparative phylogenomics. We identify at least three independent gains of the ability to engage in the lichen symbiosis, one in Trebouxiophyceae and two in Ulvophyceae, confirming the convergent evolution of the lichen symbioses. A carbohydrate-active enzyme from the glycoside hydrolase 8 (GH8) family was identified as a top candidate for the molecular-mechanism underlying lichen symbiosis in Trebouxiophyceae. This GH8 was acquired in lichenizing Trebouxiophyceae by horizontal gene transfer, concomitantly with the ability to associate with lichens fungal symbionts (LFS) and is able to degrade polysaccharides found in the cell wall of LFS. These findings indicate that a combination of gene family expansion and horizontal gene transfer provided the basis for lichenization to evolve in chlorophyte algae.

plant biology↗

An ancestral function of strigolactones as symbiotic rhizosphere signals

In flowering plants, carotenoid-derived strigolactones (SLs) have dual functions as hormones that regulate growth and development, and as rhizosphere signaling molecules that induce symbiosis with arbuscular mycorrhizal (AM) fungi. Here, we report the identification of bryosymbiol (BSB), a previously unidentified SL from the bryophyte Marchantia paleacea. BSB is also found in vascular plants, indicating that it is ancestral in land plants. BSB synthesis is enhanced at AM symbiosis permissive conditions and BSB deficient mutants are impaired in AM symbiosis. In contrast, the absence of BSB synthesis has little effect on the growth and gene expression. We show that the introduction of the SL receptor of Arabidopsis renders M. paleacea cells BSB-responsive. These results suggest that BSB is not perceived by M. paleacea cells due to the lack of cognate SL receptors. We propose that SLs originated as AM symbiosis-inducing rhizosphere signaling molecules and were later recruited as plant hormone.

plant biology↗

Integration of A Nitrate-Related Signaling Pathway in Rhizobia-Induced Responses During Interactions with Non Legume Host Arabidopsis thaliana

Nitrogen (N) is an essential macronutrient and a key cellular messenger. Plants have evolved refined molecular systems to sense the cellular nitrogen status. Exemplified by the root nodule symbiosis between legumes and symbiotic rhizobia, where external nitrate availability inhibits the interaction. However, nitrate also functions as a metabolic messenger, resulting in nitrate signaling cascades which intensively cross-talk with other physiological pathways. NIN (NODULE INCEPTION)-LIKE PROTEINS (NLPs) are key players in nitrate signaling and regulate nitrate-dependent transcription. Nevertheless, the coordinated interplay between nitrate signaling pathways and rhizobacteria-induced responses remains to be elucidated. In our study, we investigate rhizobia-induced changes in the root system architecture of the non-legume host Arabidopsis in dependence of different nitrate conditions. We demonstrate that rhizobia induce lateral root growth, and increase root hair length and density in a nitrate-dependent manner. These processes are regulated by AtNLP4 and AtNLP5 as well as nitrate transceptor NRT1.1, as the corresponding mutants fail to respond to rhizobia. On a cellular level, NLP4 and NLP5 control a rhizobia-induced decrease in cell elongation rates, while additional cell divisions occurred independent of NLP4. In summary, our data suggest that root morphological responses to rhizobia, dependent on a nutritional signaling pathway that is evolutionary related to regulatory circuits described in legumes.

plant biology↗

An ancestral signalling pathway is conserved in plant lineages forming intracellular symbioses

Plants are the foundation of terrestrial ecosystems and their colonization of land was facilitated by mutualistic associations with arbuscular mycorrhizal fungi. Following that founding event, plant diversification has led to the emergence of a tremendous diversity of mutualistic symbioses with microorganisms, ranging from extracellular associations to the most intimate intracellular associations, where fungal or bacterial symbionts are hosted inside plant cells. Through analysis of 271 transcriptomes and 122 plant genomes, we demonstrate that the common symbiosis signalling pathway controlling the association with arbuscular mycorrhizal fungi and with nitrogen-fixing bacteria specifically co-evolved with intracellular endosymbioses, including ericoid and orchid mycorrhizae in angiosperms and ericoid-like associations of bryophytes. In contrast, species forming exclusively extracellular symbioses like ectomycorrhizae or associations with cyanobacteria have lost this signalling pathway. This work unifies intracellular symbioses, revealing conservation in their evolution across 450 million years of plant diversification.

plant biology↗

The Medicago truncatula DREPP protein triggers microtubule fragmentation in membrane nanodomains during symbiotic infections

The initiation of intracellular host cell colonization by symbiotic rhizobia in Medicago truncatula requires repolarization of root hairs, which includes the re-arrangement of cytoskeletal filaments. The molecular players governing microtubule (MT) re-organization during infection remain to be discovered. Here, we identified the M. truncatula DREPP protein and investigated its functions during rhizobial infections. We show that rhizobial colonization of drepp mutant roots as well as transgenic roots over-expressing DREPP is impaired. DREPP re-localizes into symbiosis-specific membrane nanodomains in a stimulus-dependent manner. This subcellular segregation coincides with DREPP-dependent MT fragmentation and a partial loss of the ability to re-organize the MT cytoskeleton in response to rhizobia, which might relay on an interaction between DREPP and MT organizing protein SPIRAL2 (SPR2). Taken together, our results reveal that establishment of symbiotic associations in M. truncatula require DREPP in order to regulate MT reorganization during initial root hair responses to rhizobia.

plant biology↗

Cytochrome P450 26b1-mediated specification of vestibular striola and central zones is required for transient responses in linear acceleration

Each vestibular sensory epithelia of the inner ear is divided into two zones, the striola and extrastriola in maculae of otolith organs and the central and peripheral zones in cristae of semicircular canals, that differ in morphology and physiology. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, the identities of the striolar/central zones were compromised, including abnormal innervating neurons and otoconia in otolith organs. Vestibular evoked potentials (VsEP) in response to jerk stimuli were largely absent. Vestibulo-ocular reflexes and standard motor performances such as forced swimming were unaffected, but mutants had head tremors and deficits in balance beam tests that were consistent with abnormal vestibular input. Thus, degradation of RA during embryogenesis is required for patterning highly specialized regions of the vestibular sensory epithelia that may provide acute feedback about head motion.

neuroscience↗