Biology subjects

Iulianella, A.

Publications and source records attributed to Iulianella, A..

7 recordsLinked to original sources

bioRxiv2025

Impaired subgranular zone radial glia morphology and transient amplification of neural progenitors in Mllt11-deficient mice leads to increased hippocampal neurogenesis

The mammalian hippocampus derives from the cortical hem region of the forebrain and is one of the two regions in the mammalian forebrain that contains neural progenitors capable of generating new neurons in the postnatal brain. Hippocampal neural stem cells, referred to as type I progenitors, are Sox2+/GFAP+, localize along the hilar boundary region, and possess a radial glia fiber that spans the thickness of the dentate gurus. The hilar boundary region serves as a niche for the neural progenitor pool, controlling the activation of type-1 progenitors to transit amplifying type-2 neural progenitors which lose their apical adherence to the hilus as they differentiate to granule cells. The genetic regulation of this process is not fully understood and requires factors that control the mobilization of type-1 cells from their hilar niche in the subgranular zone. To that end we now report a role for Mllt11 (Af1q/Tcf7c; Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene from Chromosome 1q/T cell factor 7 co-factor), a regulator of neurite formation and migration in the cortex, in the regulation of hippocampal neurogenesis by restricting the transition of type-1 cells to transit amplifiers and neuroblasts. We previously showed that Cux2 (Cutl2) is widely expressed in the developing hippocampus, initially in the subventricular zone of the cortical hem, which generates the dentate gyrus, then in both type-1 and type-2 neural progenitors, and later in maturing granule cells of the perinatal hippocampus. To evaluate a role for Mllt11 in hippocampal neurogenesis, we used a Cux2IRESCre/+ line to generate a Mllt11 loss-of-function in perinatal hippocampal progenitors and differentiating granule cells. The loss of Mllt11 led to enlarged dentate blades dues to increased generation of NeuN+ and Calbindin+ granule cells. Explorations of the progenitor pool revealed increased transit amplifying cells due to an expanded pool of displaced Sox2+/GFAP+ deep in the dentate blades, with altered radial glial morphology. Consequently, type-1 progenitors aberrantly transitioned to amplifying progenitors and neuroblasts, resulting in enhanced granule cell neurogenesis in the postnatal hippocampus. Primary neurosphere formation assays confirmed enhanced proliferation of neural stem cells derived from Mllt11 knockout hippocampi. Taken together, the findings reported here demonstrate the critical role of Mllt11 in maintaining the hippocampal radial glial phenotype and their association within the subgranular zone-hilar niche boundary region, thereby controlling their differentiation to transit amplifiers and granule cells.

developmental biology↗

bioRxiv2025

Altered pseudostratified epithelial development of the lateral ventricle choroid plexus in Mllt11 mutants

The choroid plexuses (ChPs) are modified epithelial structures that penetrate all four cerebral ventricles and secrete cerebrospinal fluid. They consist of a central stroma that is vascularized with fenestrated blood vessels and connective tissue. The ChPs are of dual embryonic origin, with forebrain neuroepithelial cells contributing to the epithelial component and mesenchymal cells contributing to the stromal cells. The growth of the ChPs into the ventricular spaces is fueled by the migration and proliferation of neuroepithelial progenitor cells originating from the cortical hem. However, the genetic regulation of neuroepithelial progenitor (NEP) migration during ChP development is not well understood. Here we report the role of Mllt11 (Af1q/Tcf7c) in the formation of the ChP in part by regulating the migration of Otx1/2+ NEPs into the base of the fetal ChP, fueling its "treadmilling" growth into the lateral ventricle. We used Cux2iresCre/+ allele to selectively ablate Mllt11 in the developing cortical hem and its principal derivatives, the ChP and hippocampus. We discovered that Mllt11 mutants displayed thickened cuboid epithelial architecture of the ChP but maintained the epithelial organization of the outer layer of the ChP. This likely contributed to shorter lateral ventricle ChP stalks in Mllt11 cKO brains.

developmental biology↗

bioRxiv2024

Characterization of Social and Repetitive Behaviors of Mllt11/Af1q/TcF7c Conditional Knockout Mice

Mllt11 (myeloid/lymphoid or mixed-lineage leukemia translocated to chromosome 11; also known as Af1q/TcF7c) has been identified as a novel regulator of neural development, playing a role in the migration and outgrowth of cortical projection neurons. We previously reported that the conditional inactivation of the Mllt11 gene in the mouse superficial cortex resulted in reduced connectivity of the corpus callosum and white matter fiber tracts, resulting in reduced cortical thickness. However, the behavioral consequences of Mllt11 loss are unknown. Callosal abnormalities are thought to be present in 3-5% of all neurodevelopmental disorders and reduced corpus callosum volume correlates with core symptoms of autism spectrum disorder (ASD) in humans. Cortical thickness dysregulation is likewise shared among various neurodevelopmental disorders including ASD. We therefore investigated the behavioral consequences of conditional knockout of Mllt11 in upper cortical layer 2/3 projection neurons using transgenic Cux2iresCre mice. Utilizing tasks designed to reflect core ASD symptoms, we examined the behaviors of both male and female conditional knockout animals. These tests included olfaction habituation/dishabituation, three-chambered social approach, marble burying, and nestlet shredding. We found sex-dependent disruptions in social preference and nestlet shredding in animals lacking Mllt11, with the female mice presenting with more disruptions than the males. Understanding the behavioral phenotype associated with genes of interest, specifically in the context of sex differences, is crucial to individualized treatment for neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Innervation of cranial muscles requires Mllt11/Af1q/Tcf7c function during trigeminal ganglion development

The development of cranial nerves, including the trigeminal nerve, and the formation of neuromuscular junctions (NMJs) are crucial processes for craniofacial motor function. Mllt11/Af1q/Tcf7c (henceforth Mllt11), a novel type of cytoskeletal-interacting protein, has been implicated in neuronal migration and neuritogenesis during central nervous system development. However, its role in peripheral nerve development and NMJ formation remains poorly understood. This study investigates the function of Mllt11 during trigeminal ganglion development and its impact on motor innervation of the masseter muscle. We report Mllt11 expression in the developing trigeminal ganglia, suggesting a potential role in cranial nerve development. Using a conditional knockout mouse model to delete Mllt11 in Wnt1-expressing neural crest cells, we assessed trigeminal ganglion development and innervation of the masseter muscle in the jaw. Surprisingly, we find that Mllt11 loss does not affect the initial formation of the trigeminal ganglion but disrupts its cellular composition, with a reduction in the ratio of neural crest-derived Sox10+ cells relative to placode-derived Isl1/2+ cells. Furthermore, our study demonstrates that conditional Mllt11 knockout leads to reduction of neurofilament density and NMJs within the masseter muscle, indicating altered trigeminal motor innervation. Our findings show that Mllt11 regulates the cellular composition of the trigeminal ganglion and is essential for proper trigeminal motor innervation in the masseter muscle.

developmental biology↗

bioRxiv2023

Cerebellar granule cell migration and folia development requires Mllt11/Af1q

The organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of neurogenesis and neuronal migration, plays a crucial role in the development of the cerebellum, a structure exhibiting a distinct folding cytoarchitecture with cells arranged in discrete layers. Disruptions to neuronal migration can lead to various neurodevelopmental disorders, highlighting the significance of understanding the molecular regulation of lamination. Here we report a role Mllt11/Af1q/Tcf7c (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q, also known as Mllt11 transcriptional cofactor 7; henceforth referred to Mllt11) in the migration of cerebellar granule cells (GCs). We now show that Mllt11 plays a role in both tangential and radial migration of GCs. Loss of Mllt11 led to an accumulation of GC precursors in the Rhombic Lip region and a reduction in the number of GCs successfully populating developing folia. Consequently, this results in smaller folia and an overall reduction in cerebellar size. Furthermore, analysis of the anchoring centers reveals disruptions in the perinatal folia cytoarchitecture, including alterations in the Bergmann glia fiber orientation and reduced infolding of the Purkinje cell plate. Lastly, we demonstrate that Mllt11 interacts with Non-muscle Myosin IIB (NMIIB) and regulates its expression. We propose the dysregulation of NMIIB underlies altered GC migratory behavior. Taken together, the findings reported herein demonstrate a role for Mllt11 in regulating neuronal migration within the developing cerebellum, which is necessary for its proper neuroanatomical organization.

developmental biology↗

bioRxiv2022

Retinal neuroblast migration and laminar organization requires the cytoskeletal-interacting protein Mllt11

BackgroundThe vertebrate retina is an organized laminar structure comprised of distinct cell types populating three nuclear layers. During development, each retinal cell type follows a stereotypical temporal order of genesis, differentiation, and migration, giving rise to its stratified organization. Once born, the precise positioning of cells along the apico-basal (radial) axis of the retina is critical for subsequent connections to form, relying on orchestrated migratory processes. While these processes are critical for visual function to arise, the regulators of cellular migration and retinal lamination remain largely unexplored. ResultsWe report a role for a microtubule-interacting protein, Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in mammalian retinal cell migration during retinogenesis. We show that Mllt11 loss-of-function in mouse retinal neuroblasts affected the migration of ganglion and amacrine cells into the ganglion cell layer, and led to their ectopic accumulation in the inner plexiform layer. ConclusionsWe demonstrate that Mllt11 plays a critical role in the migration and lamination of neurons in the retina, and its loss impacted formation of the basal-most retinal layers.

developmental biology↗

bioRxiv2021

Mllt11 regulates the migration and neurite outgrowth of cortical projection neurons during development

The formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. There are generally two types of cortical projection neurons: those that project locally and interhemispherically, and those that project to sub-cerebral structures such as the thalamus, hindbrain, and spinal cord. The regulation of cortical projection morphologies is not yet fully understood at the molecular level. Here we report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during brain formation. We show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate, particularly during the formation of the upper or superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis we show that Mllt11 is a required for neuritogenesis and proper migration of upper layer cortical projection neurons. Loss of Mllt11 in the superficial cortex leads to a severe reduction in fibres crossing the corpus callosum, a progressive loss in the maintenance of upper layer projection neuron gene expression, and dysplasia of dendritic arborisation patterns. Proteomic analysis revealed that Mllt11 associates with cytoskeletal components including stabilized microtubules consistent with a role in neuronal migration and neuritogenesis. Taken together, our findings support a role for Mllt11 in promoting the formation of mature projection neuron morphologies and connectivity in the cerebral cortex.

developmental biology↗