Development
· 2025 Feb · PMID 39804120
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Tissue development relies on the coordinated differentiation of stem cells in dynamically changing environments. The formation of the vertebrate neural tube from stem cells in the caudal lateral epiblast is a well-charac...Tissue development relies on the coordinated differentiation of stem cells in dynamically changing environments. The formation of the vertebrate neural tube from stem cells in the caudal lateral epiblast is a well-characterized example. Despite an understanding of the signalling pathways involved, the gene regulatory mechanisms remain poorly defined. To address this, we developed a multiplexed in vivo CRISPR screening approach in chick embryos targeting genes expressed in the caudal epiblast and neural tube. This revealed a role for MLLT3, a component of the super elongation complex, in the specification of neural fate. Perturbation of MLLT3 disrupted neural tube morphology and reduced neural fate acquisition. Mutant forms of retinoic acid receptor A lacking the MLLT3 binding domain similarly reduced neural fate acquisition. Together, these findings validate an in vivo CRISPR screen strategy in chick embryos and identify a previously unreported role for MLLT3 in caudal neural tissue specification.
Rao A, Russell A, Segura-Bermudez J
… +8 more, Franz C, Dockery R, Blatnik A, Panten J, Zevallos M, McNulty C, Pietrzak M, Goldman JA
Development
· 2025 Feb · PMID 39803985
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Zebrafish have a high capacity to regenerate their hearts. Several studies have surveyed transcriptional enhancers to understand how gene expression is controlled during heart regeneration. We have identified REN (the ru...Zebrafish have a high capacity to regenerate their hearts. Several studies have surveyed transcriptional enhancers to understand how gene expression is controlled during heart regeneration. We have identified REN (the runx1 enhancer) that, during regeneration, regulates the expression of the nearby runx1 gene. We show that runx1 mRNA is reduced with deletion of REN (ΔREN), and cardiomyocyte proliferation is enhanced in ΔREN mutants only during regeneration. Interestingly, in uninjured hearts, ΔREN mutants have reduced expression of adamts1, a nearby gene that encodes a Collagen protease. This results in excess Collagen within cardiac valves of uninjured hearts. The ΔREN Collagen phenotype is rescued by an allele with Δrunx1 mutations, suggesting that in uninjured hearts REN regulates adamts1 independently of runx1. Taken together, this suggests that REN is rewired from adamts1 in uninjured hearts to stimulate runx1 transcription during regeneration. Our data point to a previously unappreciated mechanism for gene regulation during zebrafish heart regeneration. We report that an enhancer is rewired from expression in a distal cardiac domain to activate a different gene in regenerating tissue.
Kuroha K, Dočkal I, Radović U
… +6 more, Nakajima K, Hoshi I, Matsuda S, Kojitani N, Ohbo K, Tomizawa SI
Development
· 2025 Jan · PMID 39745222
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Cryptorchidism is the most frequent congenital defect in newborn males characterized by the absence of the testis from the scrotum. Approximately 90% of individuals with untreated bilateral cryptorchidism exhibit azoospe...Cryptorchidism is the most frequent congenital defect in newborn males characterized by the absence of the testis from the scrotum. Approximately 90% of individuals with untreated bilateral cryptorchidism exhibit azoospermia due to defective spermatogenesis in the affected testis. Although abnormal spermatogonial stem cell maintenance or differentiation is suggested to cause germ cell degeneration in the cryptorchid testis, the underlying molecular mechanisms remain unclear. Here, we profiled spermatogonial epigenetic landscapes using surgically induced cryptorchid testis in the mouse. We show that cryptorchidism leads to alterations in local, but not global, H3K27me3 and H3K9me3 in undifferentiated spermatogonia. Of these, the loss of H3K27me3 was correlated with activation of developmental and proapoptotic pathway genes that are repressed by the polycomb machinery in germ cells. Cryptorchid spermatogonia exhibit an increase of the H3K27me3 demethylases KDM6A and KMD6B. Furthermore, we reveal that an increased temperature leads to Kdm6a/b upregulation in germline stem cells cultured in vitro. Thus, our study suggests that temperature-dependent histone demethylation may induce mRNA dysregulation due to the partial loss of H3K27me3 in spermatogonia.
Trinh LT, Finnel RR, Osipovich AB
… +4 more, Musselman JR, Sampson LL, Wright CVE, Magnuson MA
Development
· 2025 Jan · PMID 39745200
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Expression of SRY-box transcription factor 17 (Sox17) in the endodermal region caudal to the hepatic diverticulum during late gastrulation is necessary for hepato-pancreato-biliary system formation. Analysis of an alleli...Expression of SRY-box transcription factor 17 (Sox17) in the endodermal region caudal to the hepatic diverticulum during late gastrulation is necessary for hepato-pancreato-biliary system formation. Analysis of an allelic series of promoter-proximal mutations near the transcription start site (TSS) 2 of Sox17 in mouse has revealed that gallbladder (GB) and extrahepatic bile duct (EHBD) development is exquisitely sensitive to Sox17 expression levels. Deletion of a SOX17-binding cis-regulatory element in the TSS2 promoter impairs GB and EHBD development by reducing outgrowth of the nascent biliary bud. These findings reveal the existence of a SOX17-dependent autoregulatory loop that drives Sox17 expression above a critical threshold concentration necessary for GB and EHBD development to occur, and that minor impairments in Sox17 gene expression are sufficient to impair the expression of SOX17-regulated genes in the nascent GB and EHBD system, impairing or preventing development.
Development
· 2025 Jan · PMID 39745198
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Ascidian larval muscle cells present a classic example of autonomous development. A regulatory mechanism for these cells has been extensively investigated, and the regulatory gene circuit has been documented from materna...Ascidian larval muscle cells present a classic example of autonomous development. A regulatory mechanism for these cells has been extensively investigated, and the regulatory gene circuit has been documented from maternal factors to a muscle-specific gene. In the present study, we comprehensively identified genes expressed specifically in ascidian muscle cells, and found that all of them are under control of a positive regulatory loop of Tbx6-r.b and Mrf, the core circuit identified previously. We also found that several transcription factors under control of the Tbx6-r.b/Mrf regulatory loop exhibited various temporal expression profiles, which are probably important for creating functional muscle cells. These results, together with results of previous studies, provide an exhaustive view of the regulatory system enabling autonomous development of ascidian larval muscle cells. It shows that the Tbx6-r.b/Mrf regulatory loop, but not a single gene, serves a 'master' regulatory function. This master regulatory loop not only controls spatial gene expression patterns, but also governs temporal expression patterns in ascidian muscle cells.
Vasan L, Chinchalongporn V, Saleh F
… +22 more, Zinyk D, Ke C, Suresh H, Ghazale H, Belfiore L, Touahri Y, Oproescu AM, Patel S, Rozak M, Amemiya Y, Han S, Moffat A, Black SE, McLaurin J, Near J, Seth A, Goubran M, Reiner O, Gillis J, Wang C, Okawa S, Schuurmans C
Development
· 2025 Jan · PMID 39680368
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Proneural genes are conserved drivers of neurogenesis across the animal kingdom. How their functions have adapted to guide human-specific neurodevelopmental features is poorly understood. Here, we mined transcriptomic da...Proneural genes are conserved drivers of neurogenesis across the animal kingdom. How their functions have adapted to guide human-specific neurodevelopmental features is poorly understood. Here, we mined transcriptomic data from human fetal cortices and generated from human embryonic stem cell-derived cortical organoids (COs) to show that NEUROG1 and NEUROG2 are most highly expressed in basal neural progenitor cells, with pseudotime trajectory analyses indicating that NEUROG1-derived lineages predominate early and NEUROG2 lineages later. Using ChIP-qPCR, gene silencing and overexpression studies in COs, we show that NEUROG2 is necessary and sufficient to directly transactivate known target genes (NEUROD1, EOMES, RND2). To identify new targets, we engineered NEUROG2-mCherry knock-in human embryonic stem cells for CO generation. The mCherry-high CO cell transcriptome is enriched in extracellular matrix-associated genes, and two genes associated with human-accelerated regions: PPP1R17 and FZD8. We show that NEUROG2 binds COL1A1, COL3A1 and PPP1R17 regulatory elements, and induces their ectopic expression in COs, although NEUROG2 is not required for this expression. Neurog2 similarly induces Col3a1 and Ppp1r17 in murine P19 cells. These data are consistent with a conservation of NEUROG2 function across mammalian species.
Development
· 2024 Dec · PMID 39671171
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More than 40 years ago, studies of the Drosophila engrailed and Hox genes led to major discoveries that shaped the history of developmental biology. We learned that these genes define the state of determination of cells...More than 40 years ago, studies of the Drosophila engrailed and Hox genes led to major discoveries that shaped the history of developmental biology. We learned that these genes define the state of determination of cells that populate particular spatially defined regions: the identity of segmental domains by Hox genes, and the identity of posterior developmental compartments by engrailed. Hence, the boundaries that delimit spatial domains depend on engrailed. Here, we review the engrailed field, which now includes orthologs in Drosophila and mouse, as well as many other animals. We focus on fly and mouse and highlight additional functions that span early stages of embryogenesis and neural development.
Pease NA, Denecke KM, Chen L
… +2 more, Gerges PH, Kueh HY
Development
· 2024 Dec · PMID 39655434
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How multipotent progenitors give rise to multiple cell types in defined numbers is a central question in developmental biology. Epigenetic switches, acting at single gene loci, can generate extended delays in the activat...How multipotent progenitors give rise to multiple cell types in defined numbers is a central question in developmental biology. Epigenetic switches, acting at single gene loci, can generate extended delays in the activation of lineage-specifying genes and impact lineage decisions and cell type output. Here, we analyzed a timed epigenetic switch controlling expression of mouse Bcl11b, a transcription factor that drives T-cell commitment, but only after a multi-day delay. To investigate roles for this delay in controlling lineage decision making, we analyzed progenitors with a deletion in a distal Bcl11b enhancer, which extends this delay by ∼3 days. Strikingly, delaying Bcl11b activation reduces T-cell output but enhances innate lymphoid cell (ILC) generation in the thymus by redirecting uncommitted progenitors to the ILC lineages. Mechanistically, delaying Bcl11b activation promoted ILC redirection by enabling upregulation of the ILC-specifying transcription factor PLZF. Despite the upregulation of PLZF, committed ILC progenitors could subsequently express Bcl11b, which is also needed for type 2 ILC differentiation. These results show that epigenetic switches can control the activation timing and order of lineage-specifying genes to modulate cell type numbers and proportions.
Mori Y, Smith S, Wang J
… +3 more, Eliora N, Heikes KL, Munjal A
Development
· 2025 Jan · PMID 39651757
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During inner ear semicircular canal morphogenesis in zebrafish, patterned canal-genesis zones express genes for extracellular matrix component synthesis. These include hyaluronan and the hyaluronan-binding chondroitin su...During inner ear semicircular canal morphogenesis in zebrafish, patterned canal-genesis zones express genes for extracellular matrix component synthesis. These include hyaluronan and the hyaluronan-binding chondroitin sulfate proteoglycan Versican, which are abundant in the matrices of many developing organs. Charged hyaluronate polymers play a key role in canal morphogenesis through osmotic swelling. However, the developmental factor(s) that pattern the synthesis of the matrix components and regulation of hyaluronate density and swelling are unknown. Here, we identify the transcription factor Lmx1b as a positive transcriptional regulator of hyaluronan, Versican, and chondroitin synthesis genes crucial for canal morphogenesis. We show that Versican regulates hyaluronan density through its protein core, whereas the charged chondroitin side chains contribute to the hydration of hyaluronate-containing extracellular matrices. Versican-tuned properties of hyaluronate matrices may be a broadly used mechanism in morphogenesis with important implications for understanding diseases in which these matrices are impaired, and for hydrogel engineering for tissue regeneration.
Pinheiro A, Petty CA, Stephens CE
… +10 more, Cabrera K, Palanques-Tost E, Gower AC, Marano M, Leviss EM, Boberg MJ, Mahendran J, Bock PM, Fetterman JL, Naya FJ
Development
· 2024 Dec · PMID 39612212
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The coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this...The coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this elaborate interplay are not well-defined. The imprinted Dlk1-Dio3 noncoding RNA (ncRNA) cluster has been associated with metabolism in various progenitor cells, suggesting it functions as a regulator of metabolism and cell state. Here, we directly demonstrate that the Dlk1-Dio3 ncRNA cluster coordinates mitochondrial respiration and chromatin structure to maintain proper cell state. Stable mouse muscle cell lines were generated harboring two distinct deletions in the proximal promoter region, resulting in either greatly upregulated or downregulated expression of the entire Dlk1-Dio3 ncRNA cluster. Both mutant lines displayed impaired muscle differentiation along with dysregulated structural gene expression and abnormalities in mitochondrial respiration. Genome-wide chromatin accessibility and histone methylation patterns were also severely affected in these mutants. Our results strongly suggest that muscle cells are sensitive to Dlk1-Dio3 ncRNA dosage, and that the cluster coordinately regulates metabolic activity and the epigenome to maintain proper cell state in the myogenic lineage.
Fan W, Li Z, He X
… +3 more, Wang X, Sun M, Yang Z
Development
· 2024 Nov · PMID 39591637
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22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome. Congenital heart defects are prevalent in 22q11.2DS but the etiology is still poorly understood. In this study, we aimed to gai...22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome. Congenital heart defects are prevalent in 22q11.2DS but the etiology is still poorly understood. In this study, we aimed to gain mechanistic insights into the heart defects that result from 22q11.2 deletion, with a focus on Slc25a1, which is located in the deletion segment. Whereas global knockout of Slc25a1 in mice produced a variety of heart malformations, cardiac deletion of Slc25a1 had little effect on heart development. We then found that trophoblast-specific Slc25a1 deletion recapitulated heart anomalies in the global knockout mice. Further study identified SLC25A1 as a regulator of trophoblast and placental development through modulation of histone H3K27 acetylation at the promoters and enhancers of key genes involved in trophoblast differentiation. Finally, administration of recombinant human pregnancy-specific glycoprotein 1 (PSG1), a trophoblast-derived secretory glycoprotein, partially corrected placental and embryonic heart defects. This study defines the role of SLC25A1 in heart development by regulating placental development, and provides new insights to understand the etiology of 22q11.2DS.
Development
· 2024 Dec · PMID 39584418
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Live imaging of transcription in the Drosophila embryo using the MS2 or PP7 systems is transforming our understanding of transcriptional regulation. However, insertion of MS2/PP7 stem-loops into endogenous genes requires...Live imaging of transcription in the Drosophila embryo using the MS2 or PP7 systems is transforming our understanding of transcriptional regulation. However, insertion of MS2/PP7 stem-loops into endogenous genes requires laborious CRISPR genome editing. Here, we exploit the previously described Minos-mediated integration cassette (MiMIC) transposon system in Drosophila to establish a method for simply and rapidly inserting MS2/PP7 cassettes into any of the thousands of genes carrying a MiMIC insertion. In addition to generating a variety of stem-loop donor fly stocks, we have made new stocks expressing the complementary coat proteins fused to different fluorescent proteins. We show the utility of this MiMIC-based approach by MS2/PP7 tagging of endogenous genes and the long non-coding RNA roX1, then imaging their transcription in living embryos. We also present live transcription data from larval brains, the wing disc and ovary, thereby extending the tissues that can be studied using the MS2/PP7 system. Overall, this first high-throughput method for tagging mRNAs in Drosophila will facilitate the study of transcription dynamics of thousands of endogenous genes in a range of Drosophila tissues.
Samudra SP, Park S, Esser EA
… +4 more, McDonald TP, Borges AM, Eggenschwiler J, Menke DB
Development
· 2024 Nov · PMID 39576177
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The establishment of CRISPR/Cas9 gene editing in Anolis sagrei has positioned this species as a powerful model for studies of reptilian gene function. To enhance this model, we developed an immortalized lizard fibroblast...The establishment of CRISPR/Cas9 gene editing in Anolis sagrei has positioned this species as a powerful model for studies of reptilian gene function. To enhance this model, we developed an immortalized lizard fibroblast cell line (ASEC-1) for the exploration of reptilian gene function in cellular processes. We demonstrate the use of this cell line by scrutinizing the role of primary cilia in lizard Hedgehog (Hh) signaling. Using CRISPR/Cas9 mutagenesis, we disrupted the ift88 gene, which is required for ciliogenesis in diverse organisms. We determined that loss of itf88 from lizard cells leads to an absence of primary cilia, a partial derepression of gli1 transcription, and an inability of the cells to respond to the Smoothened agonist, SAG. Through a cross-species analysis of SAG-induced transcriptional responses in cultured limb bud cells, we further determined that ∼46% of genes induced as a response to Hh pathway activation in A. sagrei are also SAG responsive in Mus musculus limb bud cells. Our results highlight conserved and diverged aspects of Hh signaling in anoles and establish a new resource for investigations of reptilian gene function.
Azzarelli R, Gillen S, Connor F
… +5 more, Lundie-Brown J, Puletti F, Drummond R, Raffaelli A, Philpott A
Development
· 2024 Dec · PMID 39575884
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The proneural transcription factor ASCL1 regulates neurogenesis and drives somatic cell reprogramming into neurons. However, not all cell types can be reprogrammed by ASCL1, raising the questions of what provides compete...The proneural transcription factor ASCL1 regulates neurogenesis and drives somatic cell reprogramming into neurons. However, not all cell types can be reprogrammed by ASCL1, raising the questions of what provides competence and how we can overcome barriers to enable directed differentiation. Here, we investigate how levels of ASCL1 and its phosphorylation modulate its activity over progressive lineage restriction of mouse embryonic stem cells. We find that inhibition of ASCL1 phosphorylation enhances reprogramming of both mesodermal and neuroectodermal cells, while pluripotent cells remain refractory to ASCL1-directed neuronal differentiation. By performing RNA-seq and ATAC-seq in neuroectoderm, we find that un(der)phosphorylated ASCL1 causes increased chromatin accessibility at sites proximal to neuronal genes, accompanied by their increased expression. Combined analysis of protein stability and proneural function of phosphomutant and phosphomimetic ASCL1 reveals that protein stability plays only a marginal role in regulating activity, while changes in amino acid charge cannot fully explain enhanced activity of the serine-proline mutant variants of ASCL1. Our work provides new insights into proneural factor activity and regulation, and suggests ways to optimize reprogramming protocols in cancer and regenerative medicine.
Li X, Liu M, Xing Y
… +6 more, Niu Y, Liu TH, Sun JL, Liu Y, Hemba-Waduge RU, Ji JY
Development
· 2024 Dec · PMID 39531377
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The Mediator complex plays a pivotal role in facilitating RNA polymerase II-dependent transcription in eukaryotes. Within this complex, the CDK8 kinase module (CKM), comprising CDK8, Cyclin C (CycC), Med12 and Med13, ser...The Mediator complex plays a pivotal role in facilitating RNA polymerase II-dependent transcription in eukaryotes. Within this complex, the CDK8 kinase module (CKM), comprising CDK8, Cyclin C (CycC), Med12 and Med13, serves as a dissociable subcomplex that modulates the activity of the small Mediator complex. Genetic studies in Drosophila have revealed distinct phenotypes associated with mutations in CKM subunits, but the underlying mechanisms have remained unclear. Using Drosophila as a model, we generated transgenic strains to deplete individually or simultaneously the four CKM subunits in all possible combinations, uncovering unique phenotypes in the eyes and wings. Depletion of CDK8-CycC enhanced E2F1 target gene expression and promoted cell-cycle progression, whereas Med12-Med13 depletion had no significant impact on these processes. Instead, depleting Med12-Med13 altered the expression of ribosomal protein genes and fibrillarin, and reduced nascent protein synthesis, indicating a severe reduction in ribosome biogenesis and cellular growth compared to the loss of CDK8-CycC. These findings reveal distinct in vivo roles for CKM subunits, with Med12-Med13 disruption having a more pronounced effect on ribosome biogenesis and protein synthesis than CDK8-CycC loss.
Development
· 2024 Nov · PMID 39514673
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A remarkable feature of limb regeneration is the ability to regenerate normal limb morphology and anatomical patterning. Although it is thought that regeneration uses similar mechanisms to those employed during developme...A remarkable feature of limb regeneration is the ability to regenerate normal limb morphology and anatomical patterning. Although it is thought that regeneration uses similar mechanisms to those employed during development, it is not well understood how this is achieved in the context of varying blastema size. In a new study, Akira Satoh, Yoshihiro Morishita and colleagues investigate the allometric scaling of blastema size and pattern expressions of key genes relative to the size of the limb stump in axolotls. To find out more about the work, we caught up with first author Saya Furukawa, and corresponding authors Akira Satoh, professor at Okayama University, and Yoshihiro Morishita, Principal Investigator at RIKEN, Japan.
Matsuoka Y, Nakamura T, Watanabe T
… +7 more, Barnett AA, Tomonari S, Ylla G, Whittle CA, Noji S, Mito T, Extavour CG
Development
· 2025 Jan · PMID 39514640
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Studies of traditional model organisms such as the fruit fly Drosophila melanogaster have contributed immensely to our understanding of the genetic basis of developmental processes. However, the generalizability of these...Studies of traditional model organisms such as the fruit fly Drosophila melanogaster have contributed immensely to our understanding of the genetic basis of developmental processes. However, the generalizability of these findings cannot be confirmed without functional genetic analyses in additional organisms. Direct genome editing using targeted nucleases has the potential to transform hitherto poorly understood organisms into viable laboratory organisms for functional genetic study. To this end, we present a method to induce targeted genome knockout and knock-in of desired sequences in an insect that serves as an informative contrast to Drosophila, the cricket Gryllus bimaculatus. The efficiency of germline transmission of induced mutations is comparable with that reported for other well-studied laboratory organisms, and knock-ins targeting introns yield viable, fertile animals in which knock-in events are directly detectable by visualization of a fluorescent marker in the expression pattern of the targeted gene. Combined with the recently assembled and annotated genome of this cricket, this knock-in/knockout method increases the viability of G. bimaculatus as a tractable system for functional genetics in a basally branching insect.
Lee J, Gleizes A, Janto NV
… +7 more, Appell LL, Sun S, Takaesu F, Webster SF, Hailstock T, Barker N, Gracz AD
Development
· 2024 Dec · PMID 39503201
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Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we modeled fISC activation...Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we modeled fISC activation in mouse intestinal organoids with doxorubicin (DXR) treatment, a chemotherapeutic known to ablate Lgr5+ aISCs in vivo. Similar fISC gene activation was observed between organoids treated with low versus high DXR, despite significantly decreased survival at the higher dose. aISCs exhibited dose-dependent loss after DXR treatment but survived at doses compatible with organoid survival. We ablated residual aISCs after DXR treatment using a Lgr52A-DTR allele and observed that aISC survival of the initial genotoxic insult is required for organoid survival following DXR treatment. These results suggest that although typical fISC genes are activated by DXR-induced injury in organoids, functional stemness remains dependent on the aISC pool. Finally, we show that human intestinal organoids require higher doses of DXR to induce loss of survival and downregulation of LGR5. Our data establish a reproducible model of DXR-induced injury in intestinal organoids and reveal differences in in vitro responses to an established in vivo damage modality.
Development
· 2024 Nov · PMID 39475047
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Homeobox genes are among the most deeply conserved families of transcription factor-encoding genes. Following their discovery in Drosophila, homeobox genes arrived on the Caenorhabditis elegans stage with a vengeance. Be...Homeobox genes are among the most deeply conserved families of transcription factor-encoding genes. Following their discovery in Drosophila, homeobox genes arrived on the Caenorhabditis elegans stage with a vengeance. Between 1988 and 1990, just a few years after their initial discovery in flies and vertebrates, positional cloning and sequence-based searches showed that C. elegans contains HOX cluster genes, an apparent surprise given the simplicity and non-segmented body plan of the nematode, as well as many other non-clustered homeobox genes of all major subfamilies (e.g. LIM, POU, etc.). Not quite 40 years later, we have an exceptionally deep understanding of homeodomain protein expression and function in C. elegans, revealing their prevalent role in nervous system development. In this Spotlight, we provide a historical perspective and a non-comprehensive journey through the C. elegans homeobox field and discuss open questions and future directions.
Inskeep KA, Crase B, Dayarathna T
… +1 more, Stottmann RW
Development
· 2024 Nov · PMID 39470011
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Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study looked at people from 12 unrelated families with variants in the gene SMPD4, a neutral sphingomyelinase that metabo...Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study looked at people from 12 unrelated families with variants in the gene SMPD4, a neutral sphingomyelinase that metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These individuals have severe developmental brain malformations, including microcephaly and cerebellar hypoplasia. The disease mechanism of SMPD4 was not known and so we pursued a new mouse model. We hypothesized that the role of SMPD4 in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells lacking SMPD4 exhibit neural progenitor cell death and have shortened primary cilia, which is rescued by adding exogenous ceramide. SMPD4 production of ceramide is crucial for human brain development.