Biology subjects

Appel, B. H.

Publications and source records attributed to Appel, B. H..

4 recordsLinked to original sources

bioRxiv2025

Epigenetic priming of neural progenitors by Notch enhances Sonic hedgehog signaling and establishes gliogenic competence

The remarkable cell diversity of multicellular organisms relies on the ability of multipotent progenitor cells to generate distinct cell types at the right times and locations during embryogenesis. A key question is how progenitors establish competence to respond to the different environmental signals required to produce specific cell types at critical developmental timepoints. We addressed this in the mouse developing forebrain, where neural progenitor cells must switch from producing neurons to making oligodendrocytes in response to increased Sonic Hedgehog (SHH) signaling during late embryogenesis. We show that progenitor responses to SHH are regulated by Notch signaling, thus permitting proper timing of the neuron-oligodendrocyte switch. Notch activity epigenetically primes genes associated with the oligodendrocyte lineage and SHH pathway, enabling amplified transcriptional responses to endogenous SHH and robust oligodendrogenesis. These results reveal a critical role for Notch in facilitating progenitor competence states and influencing cell fate transitions at the epigenetic level.

developmental biology↗

bioRxiv2023

Synchronicity in zebrafish locomotive circuit development mediated by electrical pacemaker interneurons

The earliest motor output in vertebrate animals is generated by clusters of early-born motor neurons that occupy distinct regions of the spinal cord, innervating stereotyped muscle groups. Even the simplest movements require coordinated activity across these motor pools, yet motor neurons are not directly interconnected and instead project to the periphery. Instead, emerging motor circuits might be synchronized by pacemaker interneurons. We hypothesize that pacemaker interneurons are required for synchronization of motor neuron activity throughout the spinal cord, coupling motor pools through electrical gap junctions to ultimately drive coordinated motor behavior. With functional imaging in the embryonic zebrafish spinal cord, we show that ipsilateral caudal interneurons possess periodic activity profiles prior to widespread motor circuit activity that transition to synchronized Ca2+ events in motor neurons throughout the spinal cord. Importantly, we also show that blockade of electrical gap junctions and ablation of pioneer pacemakers leads to desynchronization in developing motor circuits. Further, we use a genetic model of hyperactivity to gain critical insight into the consequences of errors in motor circuit formation and function, finding that Fragile X syndrome (FXS) model mutant zebrafish are hyperexcitable from the earliest phases of spontaneous behavior, show reduced sensitivity to blockade of electrical gap junctions, and have increased expression of the gap junction protein Connexin 36. Taken together, our work highlights the importance of pacemakers in the development of motor circuits and suggests that the origins of hyperactivity in neurodevelopmental disorders may be established during the initiation of motor circuit formation.

neuroscience↗

bioRxiv2020

The Rab11 effectors Fip5 and Fip1 regulate zebrafish intestinal development

The Rab11 apical recycling endosome pathway is a well-established regulator of polarity and lumen formation; however, Rab11-vesicular trafficking also directs a diverse array of other cellular processes, raising the question of how Rab11 vesicles achieve specificity in space, time, and content of cargo delivery. In part, this specificity is achieved through effector proteins, yet the role of Rab11 effector proteins in vivo remains vague. Here, we use CRISPR/Cas9 gene editing to study the role of the Rab11 effector Fip5 during zebrafish intestinal development. Zebrafish contain two paralogous genes, fip5a and fip5b, that are orthologs of human FIP5. We find that fip5a and fip5b mutant fish show phenotypes characteristic of microvillus inclusion disease, including microvilli defects, inclusion bodies, and lysosomal accumulation. Single and double mutant analysis suggest that fip5a and fip5b function in parallel and regulate apical trafficking pathways required for assembly of keratin at the terminal web. Remarkably, in some genetic backgrounds, the absence of Fip5 triggers protein upregulation of a closely related family member, Fip1. This compensation mechanism occurs both during zebrafish intestinal development and in tissue culture models of lumenogenesis. In conclusion, our data implicate the Rab11 effectors Fip5 and Fip1 in a trafficking pathway required for apical microvilli formation.

cell biology↗

bioRxiv2019

The RNA Binding Protein FMRP Promotes Myelin Sheath Growth

During development, oligodendrocytes in the central nervous system extend a multitude of processes that wrap axons with myelin. The highly polarized oligodendrocytes generate myelin sheaths on many different axons, which are far removed from the cell body. Neurons use RNA binding proteins to transport, stabilize, and locally translate mRNA in distal domains of neurons. Local synthesis of synaptic proteins during neurodevelopment facilitates the rapid structural and functional changes underlying neural plasticity and avoids extensive protein transport. We hypothesize that RNA binding proteins also regulate local mRNA regulation in oligodendrocytes to promote myelin sheath growth. Fragile X mental retardation protein (FMRP), an RNA binding protein that plays essential roles in the growth and maturation of neurons, is also expressed in oligodendrocytes. To determine whether oligodendrocytes require FMRP for myelin sheath development, we examined fmr1-/- mutant zebrafish and drove FMR1 expression specifically in oligodendrocytes. We found oligodendrocytes in fmr1-/-mutants developed myelin sheaths of diminished length, a phenotype that can be autonomously rescued in oligodendrocytes with FMR1 expression. Myelin basic protein (Mbp), an essential myelin protein, was reduced in myelin tracts of fmr1-/- mutants, but loss of FMRP function did not impact the localization of mbpa transcript in myelin. Finally, expression of FMR1-I304N, a missense allele that abrogates FMRP association with ribosomes, failed to rescue fmr1-/- mutant sheath growth and induced short myelin sheaths in oligodendrocytes of wild-type larvae. Taken together, these data suggest that FMRP promotes sheath growth through local regulation of translation.

neuroscience↗