Development
· 2025 Sep · PMID 40951951
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In the segmentation clock, Hes7 expression oscillates synchronously in the presomitic mesoderm (PSM), regulating periodic somite formation. Despite intensive studies, the whole regulatory gene networks of the segmentatio...In the segmentation clock, Hes7 expression oscillates synchronously in the presomitic mesoderm (PSM), regulating periodic somite formation. Despite intensive studies, the whole regulatory gene networks of the segmentation clock remain to be analysed. To identify the direct target genes of Hes7, we performed chromatin immunoprecipitation with sequencing analysis using an anti-Hes7 antibody and knocked out the identified genes from mouse embryonic stem cells carrying a Hes7 reporter. These cells were induced to differentiate into PSM-like tissue, and live imaging of Hes7 oscillations was conducted. Among the tested genes, Cdh2 knockout resulted in downregulation of fibroblast growth factor (FGF) signalling and premature cessation of Hes7 oscillations. Conversely, Cdh2 overexpression led to upregulation of FGF signalling and prolonged Hes7 oscillations. Whereas Cdh2 mRNA showed dynamic expression through repression by Hes7 oscillations, Cdh2 protein exhibited a rather steady gradient with higher levels in the posterior PSM and lower levels in the anterior PSM. Thus, Hes7-controlled Cdh2 regulates FGF signalling, leading to the proper maintenance of Hes7 oscillations, suggesting that the interplay between Hes7 and Cdh2 governs the timing mechanism of PSM differentiation.
Yoon EJ, Beltcheva M, Ali SS
… +12 more, Fu S, Yang A, Dong C, Zemke JE, Karvas RM, Chang CT, Fischer LA, Gontarz P, Zhang B, Dietmann S, Theunissen TW, Solnica-Krezel L
Development
· 2025 Sep · PMID 40888738
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The chemokine G-protein-coupled receptor CCR7 is expressed in extra-embryonic tissues of the early human embryo, including trophectoderm and its derivatives: cytotrophoblast, extravillous trophoblast (EVT) and syncytiotr...The chemokine G-protein-coupled receptor CCR7 is expressed in extra-embryonic tissues of the early human embryo, including trophectoderm and its derivatives: cytotrophoblast, extravillous trophoblast (EVT) and syncytiotrophoblast (STB). However, its function in placentation remains understudied. Here, we have generated human embryonic stem cells harboring CCR7 deletions and differentiated them into human trophoblast stem cells (hTSC), their EVT and STB derivatives, and trophoblast organoids. We found that CCR7 mutant hTSCs exhibited delayed EVT differentiation: they retained hTSC-like characteristics, and exhibited decreased epithelial-to-mesenchymal transition and cell motility. Investigation of trophoblast organoids using single cell transcriptomics showed that CCR7 mutant organoids comprised a smaller EVT, but a larger STB population, compared to wild type. Whereas CCR7 deficiency increased cell fusion during STB differentiation, excess CCR7 reduced expression of fusion-associated genes. Mechanistically, we found that CCR7 limited early STB differentiation by reducing cAMP levels. Transcriptional profiling of CCR7 mutant STBs identified reduced gene expression related to the placental viral defense. Together, our studies demonstrate that CCR7 plays multiple roles in cellular decision-making during trophoblast differentiation, promoting EVT differentiation and limiting cell fusion during early STB formation.
Fernandez RW, Digirolamo AJ, Valperga G
… +9 more, Aguilar GR, Molina-García L, Kersh RM, Wang C, Pe K, Ramadan YH, Loer C, Barrios A, Hobert O
Development
· 2025 Aug · PMID 40838983
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We explore here how neuronal cell type diversity is genetically delineated in the context of the large, but poorly studied, male-specific nervous system of the nematode Caenorhabditis elegans. Mostly during postembryonic...We explore here how neuronal cell type diversity is genetically delineated in the context of the large, but poorly studied, male-specific nervous system of the nematode Caenorhabditis elegans. Mostly during postembryonic development, the C. elegans male adds 93 male-specific neurons, falling into 25 cardinal classes, to the predominantly embryonically generated, sex-shared nervous system, comprising 294 neurons (116 cardinal classes). Using engineered reporter alleles, we investigate here the expression pattern of 40 of the 80 phylogenetically conserved C. elegans homeodomain proteins within the male-specific nervous system. Our analysis indicates that each individual neuron class is defined by unique combinations of homeodomain proteins and that the male-specific nervous system can be subdivided along the anterior/posterior axis in HOX cluster expression domains. Using a collection of newly available terminal fate markers, we undertake a mutant analysis of five homeobox genes (unc-30/Pitx, unc-42/Prop, lim-6/Lmx, lin-11/Lhx, ttx-1/Otx) and identify defects in cell fate specification and/or male copulatory defects in each of these mutant strains. Our analysis expands our understanding of the importance of homeobox genes in nervous system development and function.
Koyama E, Yao L, Saunders C
… +6 more, Mundy C, Catheline SE, Kim M, Song C, Long F, Pacifici M
Development
· 2025 Aug · PMID 40787849
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Limb synovial joints rely on a water/lubricant-filled cavity to sustain skeletal movement through life, but mechanisms generating the cavity within the primordial joint interzone during embryogenesis remain unclear. Beca...Limb synovial joints rely on a water/lubricant-filled cavity to sustain skeletal movement through life, but mechanisms generating the cavity within the primordial joint interzone during embryogenesis remain unclear. Because water accrual would be needed to create and inflate the cavity, its formation may require energy-consuming osmoregulatory mechanisms able to draw water and exert mechanical force. Our in situ hybridization and scRNAseq data reveal that interzone cells in developing mouse embryo joints strongly expressed the Na/K-ATPase ion pump genes Atp1a1, Atp1b1 and Atp1b3. There was also local and specific expression of water channel aquaporin 1 (Aqp1) and mechano-sensing genes. When pregnant mice were administered ouabain, which is a physiological glycoside that limits pump activity and osmoregulatory processes, joint cavitation in embryos was inhibited, as was lubricant gene expression. Joint development depends on signals from Indian hedgehog-expressing growth plate chondrocytes. Interference with hedgehog signaling coordinately inhibited pump, mechano-sensing and lubricant expression and cavitation. Our data provide a new understanding of joint cavitation as an energy-requiring osmoregulatory process that accrues a water-based fluid from interstitial and transcellular sources, and establishes a fluid-filled cavity in coordination with long bone development.
Brown HE, Varderesian HV, Lam O
… +2 more, Keane SA, Ryder SP
Development
· 2025 Sep · PMID 40787769
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Organisms must sense temperature and modify their physiology to survive environmental stress. Elevated temperature reduces fertility in most sexually reproducing organisms. Maternally supplied mRNAs are required for embr...Organisms must sense temperature and modify their physiology to survive environmental stress. Elevated temperature reduces fertility in most sexually reproducing organisms. Maternally supplied mRNAs are required for embryogenesis. They encode proteins that govern early embryonic patterning. RNA-binding proteins are major effectors of maternal mRNA regulation. MEX-3 is a conserved RNA-binding protein essential for anterior patterning of Caenorhabditis elegans embryos. We previously demonstrated that the mex-3 3' untranslated region (3'UTR) represses MEX-3 abundance in the germline yet is mostly dispensable for fertility. Here, we show that the 3'UTR is essential during thermal stress. Deletion of the 3'UTR causes a highly penetrant, temperature-sensitive embryonic lethality phenotype distinct from the mex-3 null phenotype. Loss of the 3'UTR decreases MEX-3 abundance specifically in maturing oocytes and early embryos during temperature stress. Dysregulation of mex-3 reprograms the thermal stress response by reducing the expression of hundreds of heat-shock genes. We propose that a major function of the mex-3 3'UTR is to buffer MEX-3 expression during fluctuating temperature, ensuring the robustness of oocyte maturation and embryogenesis.
Quinn JW, Lee MC, Van Hazel C
… +2 more, Wilson MA, Harris RE
Development
· 2025 Oct · PMID 40772709
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Tissue regeneration requires precise activation and coordination of genes, many of which are reused from development. Although key factors have been identified, how their expression is initiated and spatially regulated a...Tissue regeneration requires precise activation and coordination of genes, many of which are reused from development. Although key factors have been identified, how their expression is initiated and spatially regulated after injury remains unclear. The stress-activated MAP kinase JNK is a conserved driver of regeneration and promotes expression of genes involved in proliferation, growth and cell fate changes in Drosophila. However, how JNK selectively activates its targets in damaged tissue is not well understood. We have previously identified damage-responsive, maturity-silenced (DRMS) enhancers as JNK-activated elements that are crucial for regeneration. Here, we show that cell death is dispensable for the activation of these enhancers, which only depend on JNK and its immediate downstream effectors. One of these is JAK/STAT, which acts as a direct, additional input necessary to expand enhancer activity into the wound periphery where JNK alone is insufficient. Furthermore, we demonstrate that a threshold level of JNK is required to initiate enhancer activation. Together, our findings reveal how JNK and JAK/STAT signaling cooperate to drive spatially and temporally regulated gene expression through damage-responsive enhancers, ensuring proper regenerative outcomes.
Avdeeva M, Chalifoux M, Joyce B
… +2 more, Shvartsman SY, Posfai E
Development
· 2025 Sep · PMID 40762476
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The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in pre-implantation embryos. This decision is regulated by the subcellular...The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in pre-implantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asynchronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live-imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, which are key transcription factors of the TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate decisions in mouse development.
Kadiyala U, Sprinzak D, Monk NAM
… +7 more, Taylor SE, Verd B, Sonnen KF, Moon L, Roeder AHK, Perez-Carrasco R, Formosa-Jordan P
Development
· 2025 Jul · PMID 40748213
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Developmental biology seeks to unravel the intricate regulatory mechanisms orchestrating the transformation of a single cell into a complex, multicellular organism. Dynamical systems theory provides a powerful quantitati...Developmental biology seeks to unravel the intricate regulatory mechanisms orchestrating the transformation of a single cell into a complex, multicellular organism. Dynamical systems theory provides a powerful quantitative, visual and intuitive framework for understanding this complexity. This Primer examines five core dynamical systems theory concepts and their applications to pattern formation during development: (1) analysis of phase portraits, (2) bistable switches, (3) stochasticity, (4) response to time-dependent signals, and (5) oscillations. We explore how these concepts shed light onto cell fate decision making and provide insights into the dynamic nature of developmental processes driven by signals and gradients, as well as the role of noise in shaping developmental outcomes. Selected examples highlight how integrating dynamical systems with experimental approaches has significantly advanced our understanding of the regulatory logic underlying development across scales, from molecular networks to tissue-level dynamics.
Dady A, Davidson L, Loyer N
… +5 more, Rappich S, Findlay GM, Sanders T, Januschke J, Storey KG
Development
· 2025 Nov · PMID 40748212
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Investigation of cell behaviour and cell biological processes underlying human development is facilitated by the creation of fluorescent reporters in human pluripotent stem cells, which can be differentiated into cell ty...Investigation of cell behaviour and cell biological processes underlying human development is facilitated by the creation of fluorescent reporters in human pluripotent stem cells, which can be differentiated into cell types of choice. Here, we report use of a PiggyBac transposon-mediated stable integration strategy to engineer human pluripotent stem cell reporter lines. These express a plasma membrane-localised protein tagged with the fluorescent proteins eGFP or mKate2, the photoconvertible nuclear marker H2B-mEos3.2, or the cytoskeletal protein F-Tractin tagged with mKate2. Focussing on neural development, these lines were used to live image and quantify cell behaviours, including cell cycle progression and cell division orientation in spinal cord rosettes. Further, lipofection-mediated introduction of PiggyBac constructs into human neural progenitors labelled single cells and small cell groups within rosettes, allowing individual cell behaviours including neuronal delamination to be monitored. Finally, using the F-Tractin-mKate2 hiPSC line, actin dynamics were captured during proliferation in cortical neural rosettes. This study presents and validates new tools and techniques with which to interrogate human cell behaviour and cell biology using live-imaging approaches.
Development
· 2025 Aug · PMID 40748209
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Myocardin-related transcription factor A (Mrtfa), also known as megakaryoblastic leukemia protein (Mkl1/MAL), associates with serum response factor (Srf) to regulate transcription in response to actin dynamics; however,...Myocardin-related transcription factor A (Mrtfa), also known as megakaryoblastic leukemia protein (Mkl1/MAL), associates with serum response factor (Srf) to regulate transcription in response to actin dynamics; however, the functions of Mrtfa in vertebrate embryos remain largely unknown. Here, we show that Mrtfa is required for neural plate folding in early Xenopus embryos. Mrtfa knockdown reduced F-actin levels and inhibited apical constriction in the neural and non-neural ectoderm. By contrast, overexpression of constitutively active Mrtfa induced apical constriction in ectodermal cells via remodeling of tricellular junctions and junctional recruitment of Myosin II. We also identify potential Mrtfa target genes in embryonic ectoderm that encode actins and many regulators of actomyosin networks and junction remodeling. Our findings suggest a role for Mrtfa in the control of morphogenetic movements during neurulation. We propose that the regulation of actomyosin contractility is an essential cellular response to Mrtfa-dependent transcriptional activation.
Development
· 2025 Jul · PMID 40728647
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Endothelial cells form the inner layer of blood vessels and play key roles in circulatory system development and function. A variety of endothelial cell types have been described through gene expression and transcriptome...Endothelial cells form the inner layer of blood vessels and play key roles in circulatory system development and function. A variety of endothelial cell types have been described through gene expression and transcriptome studies; nonetheless, the transcriptional programs that specify endothelial cell fate and maintenance are not well understood. To uncover such regulatory programs, we studied the C. elegans head mesodermal cell (HMC), a non-contractile mesodermal cell bearing molecular and functional similarities to vertebrate endothelial cells. Here, we demonstrate that a Forkhead transcription factor, LET-381, is required for HMC fate specification and maintenance of HMC gene expression. DMD-4, a DMRT transcription factor, acts downstream of and in conjunction with LET-381 to mediate these functions. Independently of LET-381, DMD-4 also represses the expression of genes associated with a different, non-HMC, mesodermal fate. Our studies uncover essential roles for FoxF transcriptional regulators in endothelial cell development and suggest that FoxF co-functioning target transcription factors promote specific non-contractile mesodermal fates.
Spitzer DC, Sun WY, Rodríguez-Vargas A
… +1 more, Hariharan IK
Development
· 2025 Aug · PMID 40689564
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The growth and survival of cells depends both on their intrinsic properties and interactions with their neighbors. In a screen of genes encoding cell-surface proteins for knockdowns that affect clone size or shape in mos...The growth and survival of cells depends both on their intrinsic properties and interactions with their neighbors. In a screen of genes encoding cell-surface proteins for knockdowns that affect clone size or shape in mosaic Drosophila imaginal discs, we found that clones with reduced echinoid (ed) function are fewer and smaller, and are frequently eliminated during development. This elimination results, in significant part, from increased levels of apoptosis due to decreased Diap1 protein. We found that Hippo pathway activity is not decreased in ed mutant cells, as previously claimed, but is decreased in some of their immediate wild-type neighbors, consistent with the observed elimination of ed clones by a mechanism resembling cell competition. In contrast to the underrepresentation of ed clones, discs or compartments composed of mostly ed mutant tissue overgrow, despite having increased levels of apoptosis. The overgrowth results from a failure to arrest growth at the appropriate final size during an extended larval stage. Thus, ed has two distinct functions: an anti-apoptotic function via maintenance of Diap1 levels, and a function to arrest growth at the appropriate final size.
Pan C, Shimada K, Chang HY
… +2 more, Wang H, Ikawa M
Development
· 2025 Aug · PMID 40679056
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It is known that various testis-specific mitochondrial proteins are associated with energy metabolism and male meiosis. PDHA2 is a testis-specific mitochondrial protein, and its encoding gene is speculated to be an autos...It is known that various testis-specific mitochondrial proteins are associated with energy metabolism and male meiosis. PDHA2 is a testis-specific mitochondrial protein, and its encoding gene is speculated to be an autosomal retrogene of the progenitor X-linked Pdha1. Here, we show that Pdha2 knockout (KO) mice exhibit azoospermia due to failure at the late pachytene-diplotene transition. We found that PDHA2 interacts with PDHB and PDHA1. PDHA2 absence leads to decreased PDHB amounts and ATP levels in male germ cells. ATP reduction impairs the function of the ATPase recombination proteins RAD51 and DMC1, causing crossover formation deficiency, further resulting in double-strand break repair failure at the pachytene stage. Pdha1 expression by transgenes in Pdha2 KO germ cells rescues fertility and PDHB expression in Pdha2 KO males, confirming the functional equivalence of PDHA1 and PDHA2. Because X-linked Pdha1 expression is silenced during meiotic sex chromosome inactivation, our findings also support the hypothesis that Pdha2 was transposed from Pdha1. In summary, PDHA2 compensates for silenced PDHA1 in male germ cells, and plays a crucial role in maintaining efficient double-strand break repair for proper meiotic progression.
Brown HE, Jean-Guillaume C, Weasner BP
… +1 more, Kumar JP
Development
· 2025 Jul · PMID 40621729
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During metazoan development, chromatin plasticity and genetic regulation are tightly connected to establish proper tissue fate and patterning. Drosophila imaginal discs are excellent models to study these processes as bo...During metazoan development, chromatin plasticity and genetic regulation are tightly connected to establish proper tissue fate and patterning. Drosophila imaginal discs are excellent models to study these processes as both genetic and mechanical injury can redirect their fate during regeneration. Reducing expression of Polycomb (Pc) results in the ectopic activation of the wing selector gene vestigial (vg) which in turn interacts with its DNA-binding partner Scalloped (Sd) - this forces the eye to transform into a wing. Reductions of other Polycomb Group members alone do not phenocopy this transformation. However, knocking down Sex comb on midleg (Scm) or Scm-related gene containing four mbt domains (Sfmbt) alongside the Pax6 gene twin of eyeless (toy) enables the eye-to-wing transformation. Using high throughput sequencing we show that toy-Sfmbt and toy-Scm knockdowns alter expression of both wing selector and Hox genes. These findings provide new insights into how the fate of the eye is specified.
Kim J, Driscoll CS, Li L
… +3 more, Wilson CA, Xie W, Knott JG
Development
· 2025 Jul · PMID 40600821
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Cell fate decisions in preimplantation embryos require the coordinated expression of pluripotency and lineage-specific transcription factors. SOX2 represents the first pluripotency regulator for which expression is restr...Cell fate decisions in preimplantation embryos require the coordinated expression of pluripotency and lineage-specific transcription factors. SOX2 represents the first pluripotency regulator for which expression is restricted to the inside cells of mouse preimplantation embryos. However, the genetic mechanisms that activate the expression of zygotic Sox2 are poorly understood. Here, we report that Sox2 expression in mouse embryos is controlled by the actions of key cis-regulatory elements, including a proximal promoter and super enhancer. We show that TFAP2C, a key trophoblast lineage regulator, binds to the Sox2 proximal promoter to activate its expression. Lastly, we provide evidence that TFAP2C and the HIPPO signaling pathway cooperatively regulate Sox2 expression. In summary, this work has important implications for understanding how conventional trophoblast transcription factors, such as TFAP2C, contribute to the activation of early pluripotency genes to facilitate divergent cellular states that support lineage formation.
Development
· 2025 Jun · PMID 40576478
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During embryonic development, cell behaviors need to be tightly regulated in time and space. Yet how the temporal and spatial regulations of cell behaviors are interconnected during embryonic development remains elusive....During embryonic development, cell behaviors need to be tightly regulated in time and space. Yet how the temporal and spatial regulations of cell behaviors are interconnected during embryonic development remains elusive. To address this, we turned to zebrafish gastrulation, the process whereby dynamic cell behaviors generate the three principal germ layers of the early embryo. Here, we show that Hoxb cluster genes are expressed in a temporally collinear manner at the blastoderm margin, where mesodermal and endodermal (mesendoderm) progenitor cells are specified and ingress to form mesendoderm/hypoblast. Functional analysis shows that these Hoxb genes regulate the timing of cell ingression: under- or overexpression of Hoxb genes perturb the timing of mesendoderm cell ingression and, consequently, the positioning of these cells along the forming anterior-posterior body axis after gastrulation. Finally, we found that Hoxb genes control the timing of mesendoderm ingression by regulating cellular bleb formation and cell surface fluctuations in the ingressing cells. Collectively, our findings suggest that Hoxb genes interconnect the temporal and spatial pattern of cell behaviors during zebrafish gastrulation by controlling cell surface fluctuations.
Development
· 2025 Jun · PMID 40576477
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The temporal and spatial expression of Hox genes has been implicated in the establishment of the body plan. In their work, Yuuta Moriyama and colleagues find that spatiotemporally ordered expression of Hoxb genes regulat...The temporal and spatial expression of Hox genes has been implicated in the establishment of the body plan. In their work, Yuuta Moriyama and colleagues find that spatiotemporally ordered expression of Hoxb genes regulates dynamic cell surface fluctuations during early gastrulation in zebrafish. To know more about their work, we spoke to the first and corresponding author, Yuuta Moriyama, Assistant Professor at Aoyama Gakuin University, Japan, and Carl-Philipp Heisenberg, Professor at the Institute of Science and Technology Austria (ISTA), Austria, where the project began.
Wei Z, Zhang S, Bai K
… +11 more, Liu Y, Luan Y, Hu Z, Li Y, Qu Z, Hu X, Ding X, Liang W, Li H, He H, Tao Y
Development
· 2025 Jul · PMID 40554746
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Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two largest populations of...Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two largest populations of neocortical interneurons, innervate the soma and/or proximal dendrites, and distal dendrites of pyramidal neurons, respectively. Using PV- and SST-specific knockout mouse models, we show that PV+ interneurons require FGFR2, which responds to FGF7, to drive PV+ inhibitory presynaptic maturation on perisomatic regions of Layer V pyramidal neurons. In contrast, SST+ interneurons rely on both FGFR1 and FGFR2, which respond to FGF10 or FGF22, to promote SST+ inhibitory presynaptic maturation on distal dendrites of pyramidal neurons in cortical Layer I. Mechanistically, FGF-FGFR signaling sustains VGAT protein levels in interneurons through PP2A and Akt pathways. Together, these findings demonstrate that distinct FGF ligand-receptor combinations regulate inhibitory presynaptic differentiation by PV+ and SST+ interneurons, contributing to the formation of compartment-specific synaptic patterns.
Development
· 2025 Jun · PMID 40552536
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Autism spectrum disorder and congenital heart disease can occur together, but the mechanisms underlying this co-morbidity are unclear. In a new study, Helen Willsey and colleagues study a group of genes that are associat...Autism spectrum disorder and congenital heart disease can occur together, but the mechanisms underlying this co-morbidity are unclear. In a new study, Helen Willsey and colleagues study a group of genes that are associated with both autism and congenital heart disease. They identify the role of ciliary biology in the shared biology of both conditions. We caught up with first author Nia Teerikorpi to find out more about this work.
Teerikorpi N, McCluskey KE, Bader E
… +10 more, Lasser MC, Wang S, Nguyen CH, Schmidt JD, Kostyanovskaya E, Sun N, Dea J, Nowakowski TJ, Willsey AJ, Willsey HR
Development
· 2025 Jun · PMID 40552535
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Autism spectrum disorder (ASD) and congenital heart disease (CHD) frequently co-occur, yet the underlying molecular mechanisms of this comorbidity remain unknown. Given that children with CHD are identified as newborns,...Autism spectrum disorder (ASD) and congenital heart disease (CHD) frequently co-occur, yet the underlying molecular mechanisms of this comorbidity remain unknown. Given that children with CHD are identified as newborns, understanding which CHD variants are associated with autism could help select individuals for early intervention. Autism gene perturbations commonly dysregulate neural progenitor cell (NPC) biology, so we hypothesized that CHD genes disrupting neurogenesis are more likely to increase ASD risk. Therefore, we performed an in vitro pooled CRISPR interference screen to identify CHD genes disrupting NPC biology and identified 45 CHD genes. A cluster of ASD and CHD genes are enriched for ciliary biology, and perturbing any one of seven such genes (CEP290, CHD4, KMT2E, NSD1, OFD1, RFX3 and TAOK1) impairs primary cilia formation in vitro. In vivo investigation of TAOK1 in Xenopus tropicalis reveals a role in motile cilia formation and heart development, supporting its prediction as a CHD gene. Together, our findings highlight a set of CHD genes that may carry risk for ASD and underscore the role of cilia in shared ASD and CHD biology.