Unique morphogenetic signatures define mammalian neck muscles and associated connective tissues

ABSTRACTIn vertebrates, head and trunk muscles develop from different mesodermal populations and are regulated by distinct genetic networks. Neck muscles at the head-trunk interface remain poorly defined due to their complex morphogenesis and dual mesodermal origins. Here, we use genetically modified mice to establish a 3D model that integrates regulatory genes, cell populations and morphogenetic events that define this transition zone. We show that the evolutionary conserved cucullaris-derived muscles originate from posterior cardiopharyngeal mesoderm, not lateral plate mesoderm, and we define new boundaries for neural crest and mesodermal contributions to neck connective tissue. Furthermore, lineage studies and functional analysis of Tbx1- and Pax3-null mice reveal a unique genetic program for somitic neck muscles that is distinct from that of somitic trunk muscles. Our findings unveil the embryological and developmental requirements underlying tetrapod neck myogenesis and provide a blueprint to investigate how muscle subsets are selectively affected in some human myopathies.

Download Full-text

Unique morphogenetic signatures define mammalian neck muscles and associated connective tissues

eLife ◽

10.7554/elife.40179 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 15

Author(s):

Eglantine Heude ◽

Marketa Tesarova ◽

Elizabeth M Sefton ◽

Estelle Jullian ◽

Noritaka Adachi ◽

...

Keyword(s):

Functional Analysis ◽

3D Model ◽

Neck Muscles ◽

Genetic Networks ◽

Trunk Muscles ◽

Cell Populations ◽

Lateral Plate Mesoderm ◽

Connective Tissues ◽

Lateral Plate ◽

Developmental Program

In vertebrates, head and trunk muscles develop from different mesodermal populations and are regulated by distinct genetic networks. Neck muscles at the head-trunk interface remain poorly defined due to their complex morphogenesis and dual mesodermal origins. Here, we use genetically modified mice to establish a 3D model that integrates regulatory genes, cell populations and morphogenetic events that define this transition zone. We show that the evolutionary conserved cucullaris-derived muscles originate from posterior cardiopharyngeal mesoderm, not lateral plate mesoderm, and we define new boundaries for neural crest and mesodermal contributions to neck connective tissue. Furthermore, lineage studies and functional analysis of Tbx1- and Pax3-null mice reveal a unique developmental program for somitic neck muscles that is distinct from that of somitic trunk muscles. Our findings unveil the embryological and developmental requirements underlying tetrapod neck myogenesis and provide a blueprint to investigate how muscle subsets are selectively affected in some human myopathies.

Download Full-text

HOXA5 protein expression and genetic fate mapping show lineage restriction in the developing musculoskeletal system

The International Journal of Developmental Biology ◽

10.1387/ijdb.180214jm ◽

2018 ◽

Vol 62 (11-12) ◽

pp. 785-796

Author(s):

Miriam A. Holzman ◽

Jenna M. Bergmann ◽

Maya Feldman ◽

Kim Landry-Truchon ◽

Lucie Jeannotte ◽

...

Keyword(s):

Protein Expression ◽

Hox Genes ◽

Lineage Tracing ◽

Genetic Lineage ◽

Lateral Plate Mesoderm ◽

Embryonic Cells ◽

Connective Tissues ◽

Lateral Plate ◽

Direct Role ◽

Skeletal Patterning

HOX proteins act during development to regulate musculoskeletal morphology. HOXA5 patterns skeletal structures surrounding the cervical-thoracic transition including the vertebrae, ribs, sternum and forelimb girdle. However, the tissue types in which it acts to pattern the skeleton, and the ultimate fates of embryonic cells that activate Hoxa5 expression are unknown. A detailed characterization of HOXA5 expression by immunofluorescence was combined with Cre/LoxP genetic lineage tracing to map the fate of Hoxa5 expressing cells in axial musculoskeletal tissues and in their precursors, the somites and lateral plate mesoderm. HOXA5 protein expression is dynamic and spatially restricted in derivatives of both the lateral plate mesoderm and somites, including a subset of the lateral sclerotome, suggesting a local role in regulating early skeletal patterning. HOXA5 expression persists from somite stages through late development in differentiating skeletal and connective tissues, pointing to a continuous and direct role in skeletal patterning. In contrast, HOXA5 expression is excluded from the skeletal muscle and muscle satellite cell lineages. Furthermore, the descendants of Hoxa5-expressing cells, even after HOXA5 expression has extinguished, never contribute to these lineages. Together, these findings suggest cell autonomous roles for HOXA5 in skeletal development, as well as non-cell autonomous functions in muscle through expression in surrounding connective tissues. They also support the notion that different Hox genes display diverse tissue specificities and locations to achieve their patterning activity.

Download Full-text

Unexpected contribution of fibroblasts to muscle lineage as a mechanism for limb muscle patterning

Nature Communications ◽

10.1038/s41467-021-24157-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joana Esteves de Lima ◽

Cédrine Blavet ◽

Marie-Ange Bonnin ◽

Estelle Hirsinger ◽

Glenda Comai ◽

...

Keyword(s):

Connective Tissue ◽

Lineage Tracing ◽

Myotendinous Junction ◽

Genetic Lineage ◽

Limb Muscle ◽

Lateral Plate Mesoderm ◽

Loss Of Function ◽

Sequencing Data ◽

Lateral Plate ◽

Bmp Signalling

AbstractPositional information driving limb muscle patterning is contained in connective tissue fibroblasts but not in myogenic cells. Limb muscles originate from somites, while connective tissues originate from lateral plate mesoderm. With cell and genetic lineage tracing we challenge this model and identify an unexpected contribution of lateral plate-derived fibroblasts to the myogenic lineage, preferentially at the myotendinous junction. Analysis of single-cell RNA-sequencing data from whole limbs at successive developmental stages identifies a population displaying a dual muscle and connective tissue signature. BMP signalling is active in this dual population and at the tendon/muscle interface. In vivo and in vitro gain- and loss-of-function experiments show that BMP signalling regulates a fibroblast-to-myoblast conversion. These results suggest a scenario in which BMP signalling converts a subset of lateral plate mesoderm-derived cells to a myogenic fate in order to create a boundary of fibroblast-derived myonuclei at the myotendinous junction that controls limb muscle patterning.

Download Full-text

BMP signalling directs a fibroblast-to-myoblast conversion at the connective tissue/muscle interface to pattern limb muscles

10.1101/2020.07.20.211342 ◽

2020 ◽

Author(s):

Joana Esteves de Lima ◽

Cédrine Blavet ◽

Marie-Ange Bonnin ◽

Estelle Hirsinger ◽

Glenda Comai ◽

...

Keyword(s):

Connective Tissue ◽

Limb Development ◽

Lineage Tracing ◽

Genetic Lineage ◽

Lateral Plate Mesoderm ◽

Loss Of Function ◽

Sequencing Data ◽

Lateral Plate ◽

Myogenic Cells ◽

Bmp Signalling

AbstractPositional information driving limb muscle patterning is contained in lateral plate mesoderm-derived tissues, such as tendon or muscle connective tissue but not in myogenic cells themselves. The long-standing consensus is that myogenic cells originate from the somitic mesoderm, while connective tissue fibroblasts originate from the lateral plate mesoderm. We challenged this model using cell and genetic lineage tracing experiments in birds and mice, respectively, and identified a subpopulation of myogenic cells at the muscle tips close to tendons originating from the lateral plate mesoderm and derived from connective tissue gene lineages. Analysis of single-cell RNA-sequencing data obtained from limb cells at successive developmental stages revealed a subpopulation of cells displaying a dual muscle and connective tissue signature, in addition to independent muscle and connective tissue populations. Active BMP signalling was detected in this junctional cell sub-population and at the tendon/muscle interface in developing limbs. BMP gain- and loss-of-function experiments performed in vivo and in vitro showed that this signalling pathway regulated a fibroblast-to-myoblast conversion. We propose that localised BMP signalling converts a subset of lateral plate mesoderm-derived fibroblasts to a myogenic fate and establishes a boundary of fibroblast-derived myonuclei at the muscle/tendon interface to control the muscle pattern during limb development.

Download Full-text

Homeobox genes and connective tissue patterning

Development ◽

10.1242/dev.121.3.693 ◽

1995 ◽

Vol 121 (3) ◽

pp. 693-705 ◽

Cited By ~ 14

Author(s):

G. Oliver ◽

R. Wehr ◽

N.A. Jenkins ◽

N.G. Copeland ◽

B.N. Cheyette ◽

...

Keyword(s):

Smooth Muscle ◽

Connective Tissue ◽

Early Development ◽

Molecular Mechanisms ◽

Homeobox Genes ◽

Lateral Plate Mesoderm ◽

Lateral Plate ◽

Tissue Patterning

In vertebrates, limb tendons are derived from cells that migrate from the lateral plate mesoderm during early development. While some of the developmental steps leading to the formation of these tissues are known, little is known about the molecular mechanisms controlling them. We have identified two murine homeobox-containing genes, Six 1 and Six 2, which are expressed in a complementary fashion during the development of limb tendons. Transcripts for both genes are found in different sets of phalangeal tendons. Six 1 and Six 2 also are expressed in skeletal and smooth muscle, respectively. These genes may participate in the patterning of the distal tendons of the limb phalanges by setting positional values along the limb axes.

Download Full-text

A conserved regulatory program drives emergence of the lateral plate mesoderm

10.1101/261115 ◽

2018 ◽

Author(s):

Karin D. Prummel ◽

Christopher Hess ◽

Susan Nieuwenhuize ◽

Hugo J. Parker ◽

Katherine W. Rogers ◽

...

Keyword(s):

Smooth Muscle ◽

Transcription Factors ◽

Connective Tissue ◽

Live Imaging ◽

Lineage Tracing ◽

Lateral Plate Mesoderm ◽

Lateral Plate ◽

Mesodermal Cell ◽

Reporter Activity ◽

Vertebrate Embryo

AbstractCardiovascular lineages develop together with kidney, smooth muscle, and limb connective tissue progenitors from the lateral plate mesoderm (LPM). How the LPM initially emerges and how its downstream fates are molecularly interconnected remain unknown. Here, we isolated a pan-LPM enhancer in the zebrafish draculin (drl) gene that provides specific LPM reporter activity from early gastrulation. In toto live imaging and lineage tracing of drl-based reporters captured the dynamic LPM emergence as lineage-restricted mesendoderm field. The drl pan-LPM enhancer responds to the transcription factors EomesoderminA, FoxH1, and MixL1 that combined with Smad activity drive LPM emergence. We uncovered specific drl reporter activity in LPM-corresponding territories of several chordates including chicken, axolotl, lamprey, Ciona, and amphioxus, revealing a universal upstream LPM program. Altogether, our work provides a mechanistic framework for LPM emergence as defined progenitor field, possibly representing an ancient mesodermal cell state that predates the primordial vertebrate embryo.

Download Full-text

Banded Structures in the Connective Tissue of Meningioma

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100091159 ◽

1976 ◽

Vol 34 ◽

pp. 234-235

Author(s):

C. N. Sun ◽

H. J. White

Keyword(s):

Connective Tissue ◽

Osmium Tetroxide ◽

Uranyl Acetate ◽

Collagen Fibrils ◽

Lead Citrate ◽

Connective Tissues ◽

Native Collagen ◽

Routine Procedures

Previously, we have reported on extracellular cross-striated banded structures in human connective tissues of a variety of organs (1). Since then, more material has been examined and other techniques applied. Recently, we studied a fibrocytic meningioma of the falx. After the specimen was fixed in 4% buffered glutaraldehyde and post-fixed in 1% buffered osmium tetroxide, other routine procedures were followed for embedding in Epon 812. Sections were stained with uranyl acetate and lead citrate. There were numerous cross striated banded structures in aggregated bundle forms found in the connecfive tissue of the tumor. The banded material has a periodicity of about 450 Å and where it assumes a filamentous arrangement, appears to be about 800 Å in diameter. In comparison with the vicinal native collagen fibrils, the banded material Is sometimes about twice the diameter of native collagen.

Download Full-text