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Mesoderm

The mesoderm is the middle primary germ layer formed during gastrulation in triploblastic animal embryos, when certain cells migrate inward to lie between the ectoderm and endoderm.^[1]^[2] It differentiates into diverse cell types and structures essential for body support, movement, and internal transport, distinguishing triploblastic animals from simpler diploblastic organisms like cnidarians.^[1]^[3] In vertebrate development, mesoderm formation occurs primarily during the third week of gestation, with epiblast cells ingressing through the primitive streak to form distinct regions: axial mesoderm (including the notochord and prechordal plate), paraxial mesoderm (which segments into somites), intermediate mesoderm, and lateral plate mesoderm (dividing into somatic and splanchnic layers).^[2] Molecular specification of mesoderm involves signaling pathways such as BMP, Wnt, and FGF, which pattern the germ layer along the anterior-posterior axis based on the timing and location of cell ingress at the primitive streak.^[4] Key derivatives of the mesoderm include skeletal and cardiac muscles, bones and cartilage, connective and adipose tissues, blood cells and the hematopoietic system, endothelium lining blood and lymphatic vessels, the dermis of the skin, kidneys and gonads, and mesothelia lining body cavities.^[3]^[5] These contributions underscore the mesoderm's critical role in establishing the structural and functional framework of the vertebrate body, with disruptions in its formation linked to congenital anomalies such as musculoskeletal disorders.^[4]

Overview

Definition

The mesoderm is the middle of the three primary germ layers in triploblastic animals, positioned between the outer ectoderm and inner endoderm, and it arises during the initial stages of embryogenesis known as gastrulation.^[6]^[7]^[1] This germ layer is a defining feature of triploblastic metazoans, distinguishing them from simpler diploblastic organisms that lack it.^[8]^[9] Composed primarily of mesenchymal cells, the mesoderm features a loose, fluid arrangement that enables these cells to migrate extensively and differentiate into various connective and supportive tissues.^[10]^[11] These mesenchymal cells serve as progenitors for mesenchyme, facilitating the structural framework of the developing embryo.^[12] In amniotes, mesodermal cells originate from the epiblast layer through ingression between the epiblast and hypoblast.^[13] In amphibians, they derive from involuting cells at the lips of the blastopore.^[14] Extraembryonic mesoderm, also stemming from these origins in amniotes, contributes to membranes such as the chorion and amniotic sac.^[15] Among its derivatives, the mesoderm gives rise to essential structures like muscles and bones.^[16]

Role in Development

The mesoderm plays a pivotal role in organogenesis by providing structural support through the formation of skeletal elements, muscular tissues, and connective frameworks, while also contributing to the development of vascular systems essential for nutrient distribution and waste removal throughout the body. For instance, paraxial mesoderm derivatives include the axial skeleton as well as voluntary muscles, which enable locomotion and maintain posture.^[17] Similarly, lateral plate mesoderm gives rise to the cardiovascular endothelium and smooth muscles surrounding blood vessels, ensuring efficient circulatory function.^[18] Through inductive interactions, the mesoderm influences the differentiation of adjacent germ layers, notably by signaling the overlying ectoderm to form the neural tube via the notochord, a key axial mesodermal structure that secretes factors promoting neuroectoderm specification.^[19] Additionally, visceral mesoderm surrounding the endodermal gut tube provides patterning cues that regionalize the gastrointestinal epithelium, guiding its morphogenesis into distinct domains such as the stomach and intestines.00370-9/fulltext) The emergence of the mesoderm in bilaterian evolution marked a transformative innovation, facilitating the development of coelomic body cavities that separated internal organs from the outer body wall, thereby enabling more complex, segmented body plans with enhanced motility and organ specialization.^[20] This triploblastic organization, absent in simpler diploblastic animals, allowed for the radiation of diverse bilaterian phyla by supporting larger body sizes and intricate tissue interactions.^[21]

Formation and Patterning

Gastrulation and Induction

Gastrulation is a pivotal morphogenetic process in early vertebrate embryogenesis, during which the single-layered blastula transforms into a multilayered structure comprising ectoderm, mesoderm, and endoderm. In amniotes such as mammals, this involves the invagination, ingression, or involution of epiblast cells through the primitive streak, a transient structure that emerges along the posterior midline of the embryo. The primitive streak serves as the site of mesoderm formation, where epiblast cells undergo epithelial-to-mesenchymal transition (EMT) and migrate inward to generate the mesodermal layer, which spreads laterally from the streak to form mesodermal wings.^[22]^[23] In lower vertebrates like amphibians, gastrulation occurs via the blastopore, where similar cellular movements lead to mesoderm internalization, though the mechanisms differ in detail across species.^[7] Mesoderm specification is induced by signaling molecules emanating from organizer regions, which establish the initial fates of presumptive mesodermal cells. In vertebrates, nodal-related factors such as Nodal and Activin, members of the TGF-β superfamily, play a central role in this induction by activating Smad-dependent pathways in responding epiblast or animal cap cells. These signals, secreted from the organizer (e.g., the node in mammals or Spemann-Mangold organizer in amphibians), promote the expression of mesoderm-specific genes like Brachyury (T) and initiate EMT in ingressing cells.^[24]^[25] The concentration and duration of Nodal/Activin signaling determine the dorsoventral identity of the induced mesoderm, with higher levels favoring dorsal fates.^[26] Fate mapping studies reveal that presomitic mesoderm (PSM) progenitors ingress through specific regions of the primitive streak, with their positioning along the streak's anteroposterior axis dictating subsequent contributions to paraxial structures. In mouse embryos at 7.5 days of gestation, cells entering at the posterior primitive streak give rise to lateral and extraembryonic mesoderm, while mid- and anterior streak ingressors form axial and paraxial PSM, respectively. These late-ingressing cells, particularly those from the posterior primitive streak, represent neuromesodermal progenitors (NMPs), which are bipotent and contribute to both the presomitic mesoderm and the posterior neural tube during body axis elongation.^[27] These mappings, achieved through vital dye labeling or genetic lineage tracing, underscore the orderly allocation of cells during gastrulation, ensuring proper anteroposterior patterning.^[28] Species-specific variations highlight conserved yet adapted mechanisms of mesoderm induction. In Xenopus laevis, the Nieuwkoop center in the dorsal vegetal pole induces mesoderm in overlying marginal zone cells via vegetal-derived signals, including nodal-related proteins like Xnr1 and Xnr2, which initiate endomesoderm formation prior to organizer establishment.^[29] This two-step induction—first mesoderm specification by the Nieuwkoop center, then organizer formation—differs from the more integrated primitive streak dynamics in amniotes but achieves similar trilaminar organization. Subsequent patterning by gradients such as BMP refines these initial fates along the body axes.^[30]

Axial Patterning and Subdivision

The axial mesoderm, comprising the notochord and prechordal plate, emerges as a critical derivative during early embryonic development and plays an essential role in organizing the surrounding mesodermal tissues. The notochord forms posteriorly from the organizer region, extending along the midline to provide structural support and signaling cues, while the prechordal plate develops anteriorly to influence head structures. These axial structures are specified through Nodal signaling gradients that pattern the organizer along the anterior-posterior axis, with higher anterior Nodal levels promoting prechordal mesoderm and posterior levels favoring notochord formation.^[31] Following axial mesoderm formation, the nascent mesoderm is subdivided into distinct domains along the mediolateral axis: paraxial mesoderm positioned dorsally and medially, intermediate mesoderm located laterally to the paraxial domain, and lateral plate mesoderm situated ventrally. This subdivision is primarily governed by gradients of bone morphogenetic protein (BMP) signaling, where low BMP levels in dorsal regions favor paraxial mesoderm, intermediate BMP levels specify the intermediate domain, and high BMP levels promote lateral plate mesoderm. In chick embryos, for instance, BMP4 from lateral ectoderm and ventral endoderm establishes this gradient, with antagonists like Noggin and Chordin secreted by the dorsal midline (including the notochord) inhibiting BMP to refine dorsal identities.^[32]00424-8) Dorsal-ventral patterning of the mesoderm is further mediated by BMP/Chordin interactions originating from the notochord and other dorsal organizers. Chordin, produced by the notochord and prechordal mesoderm, directly binds and inhibits BMP4, creating a ventral-high BMP gradient that dorsalizes adjacent mesoderm by reducing BMP activity in medial regions. This antagonism ensures proper specification of dorsal mesodermal fates, such as somitic precursors in paraxial mesoderm, while allowing ventral fates like blood islands in lateral plate mesoderm. Experimental evidence from Xenopus shows that Chordin overexpression dorsalizes ventral mesoderm, confirming its role in this binary opposition.80132-4)^[33] Along the anterior-posterior axis, mesodermal domains are patterned through collinear Hox gene expression and retinoic acid (RA) signaling, which establish positional identity from head to tail. Hox genes are activated in a nested, 3'-to-5' manner, with anterior Hox paralogs (e.g., Hoxa1) expressed in head mesoderm and posterior ones (e.g., Hoxd13) in tail regions, directly influencing mesodermal subdivision and fate. RA, synthesized in the posterior mesoderm, diffuses anteriorly to activate these Hox clusters via retinoic acid response elements, thereby coordinating A-P patterning across paraxial, intermediate, and lateral plate domains. In zebrafish, RA signaling refines posterior mesoderm territories after initial BMP-mediated broad patterning, highlighting the sequential integration of these pathways.^[34]

Paraxial Mesoderm

Somitogenesis

Somitogenesis is the process by which the unsegmented paraxial mesoderm, known as the presomitic mesoderm (PSM), undergoes periodic segmentation to form somites, which are paired blocks of tissue arrayed along the anterior-posterior axis of the neural tube in vertebrate embryos. This segmentation establishes the metameric pattern essential for the development of the vertebral column, ribs, and body wall musculature. The segmentation process is governed by the clock and wavefront model, first proposed theoretically and later substantiated molecularly, in which a molecular oscillator (the "clock") interacts with a signaling gradient (the "wavefront") to determine the timing and position of somite boundaries. The molecular clock consists of oscillatory gene expression cycles in PSM cells, with key genes such as Hes7 exhibiting cyclic activation and repression approximately every 2 hours in mice. These oscillations, driven by negative feedback loops involving Notch, Wnt, and FGF signaling, propagate as traveling waves from the posterior to anterior PSM, synchronizing cellular states for boundary formation.^[35] The wavefront is defined by posterior-to-anterior decreasing gradients of fibroblast growth factor (FGF) and Wnt signaling, which progressively mature PSM cells by inhibiting differentiation in posterior regions while permitting it anteriorly. As the wavefront sweeps posteriorly, cells in a permissive anterior zone arrest clock oscillations and activate Mesp2, a transcription factor that specifies somite polarity and enforces boundaries by suppressing Notch signaling in anterior cells while activating it in posterior ones, thereby creating a clear interface for somite cleavage.^[36] During somite formation, mesenchymal cells in the anterior PSM undergo a mesenchymal-to-epithelial transition to assemble into epithelial somites, involving cell polarization, adhesion via cadherins, and cytoskeletal reorganization mediated by factors like Paraxis. Subsequently, somites contribute to the vertebral column through resegmentation, where the mesenchymal sclerotome halves from adjacent somites recombine across boundaries, shifting the vertebral pattern by half a somite relative to the original somite positions, as demonstrated in chick-quail chimera experiments.^[36] Mutations disrupting the segmentation clock, such as in HES7, lead to spondylocostal dysostosis, a congenital disorder characterized by irregular vertebral segmentation and rib fusions due to desynchronized oscillations and malformed somites.^[35]

Derivatives

Somites derived from the paraxial mesoderm differentiate into three main compartments: the sclerotome, myotome, and dermatome, each contributing to specific tissues in the developing embryo.^[36] The sclerotome, formed from the ventral-medial portion of the somite, gives rise to the axial skeleton, including the vertebrae and ribs. These cells undergo resegmentation, where anterior and posterior halves from adjacent somites combine to form individual vertebral bodies. Sclerotome development is induced by signals such as Sonic hedgehog (Shh) from the notochord and floor plate, leading to expression of genes like Pax1 and eventual chondrogenesis and ossification.^[36] The myotome, originating from the medial and lateral edges of the dermomyotome (the dorsal epithelial portion of the somite), differentiates into skeletal muscle precursors. The medial myotome forms epaxial muscles of the back (e.g., erector spinae), while the lateral myotome contributes to hypaxial muscles of the body wall, limbs, and diaphragm. Myogenesis is regulated by signaling pathways including Wnt from the dorsal neural tube and BMP4 from the lateral plate mesoderm.^[36] The dermatome, the central region of the dermomyotome, develops into the dermis of the dorsal skin. These cells migrate dorsolaterally to form connective tissue underlying the epidermis, influenced by factors such as neurotrophin-3 (NT-3). In addition to these primary derivatives, somites contribute to other structures like the meninges and endothelial cells in some regions.^[36]

Intermediate Mesoderm

Formation

The intermediate mesoderm originates during gastrulation as a narrow, longitudinal strip of unsegmented mesenchyme positioned between the paraxial mesoderm (which forms somites) and the lateral plate mesoderm along the anteroposterior axis of the vertebrate embryo. This region emerges ventral to the somites in the caudal trunk and is characterized by its mesenchymal composition, distinguishing it from the segmented paraxial mesoderm.^[37] Patterning signals from adjacent somites contribute to its initial specification, ensuring proper positioning relative to other mesodermal domains. Within this strip, the intermediate mesoderm undergoes organization into paired nephrotomes, which are transient epithelial structures that form along the embryonic length.^[37] These nephrotomes arise sequentially from anterior to posterior regions and represent the earliest condensations of intermediate mesoderm cells, marking the onset of urogenital patterning. The nephrotomes segment and canalize to give rise to the nephric ducts, which elongate caudally and serve as scaffolds for further mesodermal organization.^[37] Cells of the intermediate mesoderm migrate toward the forming nephric duct, condensing around it to establish a coherent longitudinal structure. In mammals, this duct is known as the Wolffian duct, and the condensation process involves mesenchymal-to-epithelial transitions that stabilize the intermediate mesoderm's position adjacent to the somites.^[37] This migration ensures the duct's extension from the anterior pronephric region to more posterior domains, maintaining bilateral symmetry. The formation of intermediate mesoderm and its nephric structures is highly conserved across vertebrates, underpinning the evolutionary progression of kidney development from the simple pronephros in basal species to the complex metanephros in mammals.^[38] This conservation reflects shared mechanisms of mesodermal induction and duct elongation that have persisted since early vertebrate divergence.

Derivatives

The intermediate mesoderm gives rise to the urogenital system, including the kidneys, gonads, and their associated duct systems. It develops three successive kidney forms: the pronephros, mesonephros, and metanephros. The pronephros forms first as a transient structure with rudimentary tubules that degenerate early in amniotes, including mammals. In humans, it appears around day 22 of gestation but is non-functional.^[37] The mesonephros develops next, producing approximately 30 tubules by day 25 in human embryos. It functions temporarily in excretion and, in males, contributes to gametogenesis; its nephric (Wolffian) duct persists as the epididymis, vas deferens, and seminal vesicles. In females, it largely regresses. The mesonephros also provides hematopoietic stem cells during early development.^[37] The metanephros, the permanent kidney, arises from interactions between the ureteric bud (an outgrowth of the nephric duct) and the metanephric mesenchyme derived from intermediate mesoderm. This reciprocal induction leads to branching of the ureteric bud into collecting ducts and differentiation of mesenchyme into nephrons, establishing the adult renal structure by around week 10 in humans.^[37] Additionally, the intermediate mesoderm forms the gonadal ridges adjacent to the mesonephros, which develop into the ovaries or testes. It contributes the stromal cells, connective tissues, and supporting structures of the gonads, with sex-specific differentiation directed by genetic factors such as the SRY gene on the Y chromosome. The adrenal cortex also originates from intermediate mesoderm coelomic epithelium.^[37]

Lateral Plate Mesoderm

Layering and Regionalization

The lateral plate mesoderm undergoes intraembryonic splitting during early vertebrate embryogenesis, separating horizontally into two distinct layers: the dorsal somatic (also known as parietal) mesoderm, which lies adjacent to the ectoderm, and the ventral splanchnic (also known as visceral) mesoderm, which lies adjacent to the endoderm.^[18] This bifurcation occurs progressively in an anteroposterior direction and is governed by inductive signals from the overlying ectoderm, which promotes the somatic fate through bone morphogenetic protein (BMP) signaling, while the splanchnic layer retains its visceral identity.^[39] The process establishes a foundational organization for body cavity development, independent of somitic segmentation patterns observed in other mesodermal regions.^[39] Between these somatic and splanchnic layers, a fluid-filled cavity emerges, known as the intraembryonic coelom, which initially forms as small spaces that coalesce and expand from the prospective neck region posteriorly along the embryo's axis.^[18] In mammals, this coelom later partitions into specialized compartments, including the pericardial, pleural, and peritoneal cavities, through septation by mesodermal folds.^[18] The coelom's formation facilitates the separation of body wall structures from visceral organs, enabling independent growth and movement during organogenesis.^[39] Along the anteroposterior axis, the lateral plate mesoderm exhibits regionalization, with the anterior portion primarily contributing to cardiac structures via the splanchnic layer, where progenitor cells express markers such as Nkx2.5 and Gata4 to form myocardial and endocardial tissues.^[40] In contrast, the posterior region supports the development of gut-associated mesenteries, where both somatic and splanchnic layers integrate to suspend and anchor the digestive tract, influenced by posterior-specific signals like those involving Sox17.^[40] This anterior-posterior patterning arises from early axial signaling gradients, ensuring domain-specific fates without segmentation.^[41] Extensions of the lateral plate mesoderm also contribute to extraembryonic structures, particularly in amniotes, where posterior portions give rise to the allantois—a vascularized sac involved in gas exchange and waste removal—and the chorion, which forms part of the placental interface through mesodermal contributions to the chorionic mesothelium.^[42] These extraembryonic derivatives originate from the same mesodermal progenitors as the intraembryonic lateral plate, supporting embryonic nutrition and respiration via connections to the umbilical vasculature.^[43]

Derivatives

The lateral plate mesoderm differentiates into two primary layers, the somatic and splanchnic, each giving rise to distinct tissues that support structural and visceral functions in the body. The somatic layer, adjacent to the ectoderm, contributes to the musculoskeletal elements of the body wall and appendages. Specifically, it forms the connective tissues and skeletal components of the limbs and girdles, including the bones of the pectoral and pelvic girdles as well as the long bones of the limbs, through a process regulated by Hox gene expression that establishes anterior-posterior patterning along the limb axis.^[18]^[44] Additionally, this layer generates the skeletal muscles of the body wall, such as those in the abdominal and thoracic regions, providing support and mobility.^[18] In contrast, the splanchnic layer, positioned adjacent to the endoderm, primarily forms cardiovascular and visceral structures. It gives rise to the myocardium of the heart, comprising the muscular walls of the atria and ventricles derived from cardiogenic mesoderm precursors.^[18] The endocardium, the inner endothelial lining of the heart chambers, originates from delaminated cells within this cardiogenic region and integrates with the vascular endothelium.^[18] Furthermore, the splanchnic layer contributes to the smooth muscle layers surrounding the gut and associated blood vessels, facilitating peristalsis and vascular tone.^[40] Both layers participate in forming the serous membranes that line the body's major cavities. The somatic layer produces the parietal layers of the pericardium (surrounding the heart), pleura (encasing the lungs), and peritoneum (lining the abdominal cavity), while the splanchnic layer forms the corresponding visceral layers that directly cover the organs. These membranes secrete lubricating fluid to reduce friction during organ movement.^[45] Extraembryonic portions of the splanchnic mesoderm are critical for hematovascular development. Hemangioblasts, bipotent progenitors arising in blood islands within this region, differentiate into hematopoietic stem cells that produce blood cells and angioblasts that form the endothelium of blood vessels.^[18] This process establishes the initial circulatory network supporting embryonic nutrition.^[46]

Molecular Regulation

Signaling Pathways

The formation and patterning of mesoderm during gastrulation and subsequent development are orchestrated by a suite of extracellular signaling pathways that provide spatial and temporal cues for cell fate specification across paraxial, intermediate, and lateral plate domains. These signals, emanating from organizers such as the node and notochord, establish gradients that dictate regional identities, with interactions between pathways ensuring precise boundaries and differentiation outcomes.^[47] Nodal and Activin signaling, members of the TGF-β superfamily, play a pivotal role in the initial induction of mesoderm from epiblast cells during gastrulation. Expressed in the primitive streak and node, Nodal ligands activate Smad2/3-dependent transcription to promote mesendodermal fates, with signaling intensity determining the dorsoventral character of the induced mesoderm. Higher doses of Nodal or Activin favor dorsal mesoderm formation (e.g., notochord and paraxial precursors), while lower concentrations drive ventral mesoderm (e.g., lateral plate and blood progenitors), as demonstrated in explant assays where graded ligand exposure yields distinct gene expression profiles.^[48]^[49]^[50] BMP signaling, primarily through BMP4 and BMP7, exerts a ventralizing influence on mesoderm, promoting the specification of lateral plate mesoderm while suppressing paraxial fates in ventral regions. This pathway operates via gradients highest in lateral and ventral domains, where it activates Smad1/5/8 to induce ventral-specific markers; however, dorsal inhibition by antagonists like Noggin and Chordin, secreted from the node and dorsal mesoderm, restricts BMP activity to allow paraxial mesoderm formation. Noggin binds directly to BMPs, preventing receptor interaction and thus enabling dorsal paraxial identity, as evidenced by loss-of-function studies showing ectopic ventralization upon antagonist depletion.^[51]^[52]^[53] In the presomitic mesoderm (PSM), Wnt and FGF signaling pathways maintain progenitor proliferation and establish posterior-to-anterior gradients essential for somitogenesis timing. FGF8 and Wnt3a, expressed in posterior PSM, form opposing gradients that delay differentiation anteriorly; high posterior levels sustain cell proliferation and undifferentiated states via ERK and β-catenin activation, while attenuation anteriorly permits maturation. These gradients interact synergistically, with FGF acting upstream to modulate Wnt responsiveness, ensuring progressive segmentation without overt cell cycle exit.^[47]^[54]^[55] Sonic hedgehog (Shh), secreted from the notochord and ventral neural tube, provides ventralizing cues to adjacent somites, promoting sclerotome specification within paraxial mesoderm. This signal diffuses to form a ventral-high gradient that induces Shh-responsive genes in medial somite regions, counteracting dorsalizing influences and partitioning somitic derivatives along the dorsoventral axis.^[56]^[57]^[58] These extracellular pathways converge on downstream transcription factors to translate signals into gene regulatory networks, though their primary roles lie in upstream patterning.^[47]

Transcription Factors and Gene Expression

The development of the mesoderm is tightly regulated by a network of transcription factors that control gene expression patterns essential for differentiation and patterning. These factors respond to upstream signaling cues, such as Wnt pathways, to orchestrate the spatial and temporal specification of mesodermal derivatives.^[59] Hox genes, organized in four clusters (HoxA, HoxB, HoxC, and HoxD), play a central role in establishing anterior-posterior identity within the paraxial mesoderm, particularly in determining regional somite fates. Expressed in a collinear manner along the body axis, Hox genes confer positional information to somites, influencing their differentiation into structures like vertebrae with distinct morphologies; for instance, Hox6 paralogs specify cervical vertebrae, while Hox9-10 regulate thoracic identity.^[60] Mutations in Hox genes disrupt axial patterning, leading to homeotic transformations where one vertebral type is replaced by another.^[61] Members of the Pax and Sox transcription factor families are critical for somite subcompartmentalization and subsequent tissue specification. Pax3 and Pax7, expressed in the dermomyotome, drive myogenesis by regulating the migration and proliferation of myogenic progenitor cells from the somites to limb and body wall muscles.^[62] In Pax3/Pax7 double mutants, skeletal myogenesis is severely impaired, highlighting their redundant yet essential roles in maintaining myogenic regulatory factor expression like MyoD and Myf5.^[63] Similarly, Sox9, a key Sox family member, is required for chondrogenesis in the sclerotome, where it promotes mesenchymal condensation and cartilage formation by activating genes such as Col2a1 and Acan.^[64] Sox9-null mice exhibit complete failure of chondrocyte differentiation, underscoring its indispensable function in the sclerotomal lineage.^[65] In somitogenesis, oscillatory gene expression driven by the segmentation clock involves Her/Hes family transcription factors, which generate rhythmic waves of activity in the presomitic mesoderm to time somite formation. Hes/Her genes, such as Hes7 in mice, form negative feedback loops that oscillate with a period of approximately 2 hours, repressing their own transcription and that of downstream targets to create periodic domains.^[66] These oscillations synchronize across cells via Notch signaling, ensuring coordinated segmentation.^[67] Mesp transcription factors, including Mesp1 and Mesp2, act downstream of the clock to define somite boundaries by activating boundary-specific genes like Dll1 in the anterior presomitic mesoderm.^[68] In Mesp2 mutants, somite boundaries fail to form properly, resulting in fused somites and disrupted rostro-caudal polarity.^[69] Domain-specific transcription factors further refine mesodermal fates in distinct regions. Lim1 (Lhx1), expressed in the intermediate mesoderm, is essential for its differentiation into nephrogenic structures, regulating genes like Pax2 and Wt1 to initiate kidney progenitor formation.^[70] Lhx1 knockout disrupts intermediate mesoderm integrity, preventing urogenital system development.^[71] In the lateral plate mesoderm, Tbx factors such as Tbx5 and Tbx20 promote cardiogenesis by driving expression of cardiac-specific genes like Nkx2.5 and Gata4 in the heart fields.^[72] Tbx5 mutations cause congenital heart defects, illustrating its role in chamber specification and conduction system formation.^[59]

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Hox genes are important for integrating and patterning musculoskeletal tissues in the limb, and are restricted to specific limb regions during development.
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The lateral plate mesoderm - PMC - PubMed Central - NIH
Jun 19, 2020 · Endothelium and blood arise, at least partially, from bipotent hemangioblasts, as well as from fate-restricted angioblasts and hematopoietic ...
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Embryonic Period (Weeks 3-8)
Lateral mesoderm. Sternum, clavicle, scapula, pelvis, and bones of the limbs. Serous membranes of body cavities. Lamina propria, muscularis mucosae, submucosa, ...
[38]
Molecular and Developmental Biology of the Hemangioblast - PMC
The hemangioblast is now used to denominate a progenitor cell with the capacity to give rise to both endothelial and hematopoietic progenitors. By analyzing ...
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Intermediate Mesoderm - Developmental Biology - NCBI Bookshelf
The intermediate mesoderm generates the urogenital system—the kidneys, the gonads, and their respective duct systems. Saving the gonads for our discussion ...Missing: embryology | Show results with:embryology
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Coelom formation: binary decision of the lateral plate mesoderm is ...
Sep 15, 1999 · The coelom is lined by two different tissue components, somatopleure and splanchnopleure, which are derived from the lateral plate region. Thus, ...
[42]
Development and evolution of the lateral plate mesoderm ...
Nov 1, 2011 · First, the lateral plate mesoderm is regionalized into the cardiac mesoderm (CM) and the posterior lateral plate mesoderm (PLPM). Second, in the ...
[43]
Distinct mesoderm migration phenotypes in extra-embryonic and ...
Apr 5, 2019 · All mesoderm, including the extra-embryonic mesoderm, is of embryonic epiblast origin. ... body and an apical thin projection (Figure 3a).
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The mouse allantois: new insights at the embryonic–extraembryonic ...
Genesis of the allantois involves formation of the primary germ layer, mesoderm, which underpins development of the entire circulatory system in both the fetus ...
[45]
Signaling Gradients during Paraxial Mesoderm Development - PMC
The sequential formation of somites along the anterior-posterior axis is under control of multiple signaling gradients involving the Wnt, FGF, and retinoic acid ...<|control11|><|separator|>
[46]
Nodal-related signals induce axial mesoderm and dorsalize ...
Xnrs and mouse nodal function as dose-dependent dorsoanterior and ventral mesoderm inducers in whole embryos and explanted animal caps.
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Activin/Nodal signalling in stem cells - Company of Biologists journals
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Dose-dependent Nodal/Smad signals pattern the early mouse embryo
Nodal signals establish initial proximal-distal polarity and the anterior-posterior body axis, and during gastrulation, specify mesodermal and endoderm ...
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Noggin-mediated antagonism of BMP signaling is required for ...
Chordin also antagonizes BMP signaling by directly binding BMP proteins ... Noggin may cooperate with Shh in patterning the somitic mesoderm. We ...
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Chordin forms a self-organizing morphogen gradient in the ... - PNAS
We report that Chordin protein forms a dorsal-to-ventral gradient in the embryo. This gradient is located in a narrow space containing extracellular matrix ( ...
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Pattern formation: A new twist to BMP signalling - Cell Press
As a consequence, the inhibition of BMP4 by Chordin (represented by the red T bars) decreases with increasing distance from the dorsal mesoderm, establishing a ...
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FGF signaling acts upstream of the NOTCH and WNT signaling ...
Nov 15, 2007 · The wavefront has been shown to involve a posterior gradient of Wnt and FGF/MAPK activity opposed to a retinoic acid (RA) gradient, which ...
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A Gradient of Glycolytic Activity Coordinates FGF and Wnt Signaling ...
A beta-catenin gradient links the clock and wavefront systems in mouse embryo ... FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis.
[54]
Neural tube development depends on notochord-derived sonic ...
Sonic hedgehog (Shh), produced in the notochord and floor plate, is necessary for both neural and mesodermal development. To reach the myotome, Shh has to ...
[55]
In Vivo Regulation of Somite Differentiation and Proliferation by ...
In vertebrates, somite differentiation is mediated in part by Sonic Hedgehog (Shh), secreted by the notochord and the floor plate. However, Shh-null mice ...Missing: ventralizes | Show results with:ventralizes
[56]
A gradient of Shh establishes mutually repressing somitic cell fates ...
Abstract. Wnt and Sonic Hedgehog (Shh) signals are known to pattern the somite into dermomyotome, myotome and sclerotomal cell fates.Missing: ventralizes | Show results with:ventralizes
[57]
T-box transcription factors and their roles in regulatory hierarchies in ...
Nov 15, 2005 · Here, we review T-box gene function during mammalian heart development in the light of new insights into heart morphogenesis. We see for the ...
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Hox patterning of the vertebrate axial skeleton - Wellik - 2007
Aug 8, 2007 · This review summarizes genetic and embryologic findings regarding the role of Hox genes in establishing axial morphologyHox Expression · Hox Function · Conclusion: The Nature Of...
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Hox genes in development and beyond
Jan 16, 2023 · Hox genes are transcription factors essential for bilaterian development, regulated spatially and temporally, and have roles throughout life.Hox protein structure and... · Regional specificity and... · Continuing roles for Hox...
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Review PAX3 and PAX7 as upstream regulators of myogenesis
Both factors are key regulators of myogenesis where Pax3 plays a major role during early skeletal muscle formation in the embryo while Pax7 predominates during ...
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Master regulators of skeletal muscle lineage development and ...
Oct 1, 2021 · The major regulators of trunk and limb muscle specification are the paired-homeobox transcription factors PAX3 and PAX7.
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The transcription factor Sox9 has essential roles in successive steps ...
We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway.
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Control of chondrogenesis by the transcription factor SOX9
Aug 9, 2025 · This review discusses the molecular properties and mechanisms of Sry-related high-mobility-group box (Sox) transcription factor, Sox9, in ...
[64]
structure, function and dynamics of the vertebrate segmentation clock
Feb 15, 2012 · The segmentation clock is an oscillating genetic network thought to govern the rhythmic and sequential subdivision of the elongating body ...
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Oscillatory control of embryonic development - PMC - PubMed Central
May 10, 2024 · According to this model, the primary role of the Hes/Her proteins in somite boundary determination is to periodically decrease ppERK levels.
[66]
Segmental border is defined by the key transcription factor Mesp2 ...
Mar 29, 2007 · The initial Mesp2 expression appears as a single band, occupying approximately one somite length, and the caudal half of its expression is ...
[67]
Zebrafish Mesp family genes, mesp-a and mesp-b are segmentally ...
Abstract. Segmentation of a vertebrate embryo begins with the subdivision of the paraxial mesoderm into somites through a not-well-understood process.
[68]
Lim1 Activity Is Required for Intermediate Mesoderm Differentiation ...
LIM Homeobox Gene 1 (Lhx1) Lhx1 (Lim1) is the most extensively studied gene in a range of animals. Lhx1 is expressed in intermediate mesoderm, mesonephros ...
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Advances in early kidney specification, development and patterning
Dec 1, 2009 · The signals that induce the expression of IM-specific genes, such as Lhx1 and Pax2, are present along the entire body axis, but the IM-specific ...Early regionalization · The metanephric mesenchyme · Patterning of the nephron
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T‐box genes and heart development: Putting the “T” in heart
Dec 3, 2004 · These analyses suggest that T-box genes act together to promote cardiac differentiation and gene expression, but do not indicate critical roles ...