Martin J. Cohn

University of Florida | UF · Department of Molecular Genetics and Microbiology

Background The embryonic renal stroma consists of multiple molecularly distinct cell subpopulations, the functional significance of which is largely unknown. Previous work has demonstrated that the transcription factors YAP and TAZ play roles in the development and morphogenesis of the nephrons, collecting ducts, and nephron progenitor cells. Meth...

Division of the dentition into morphologically distinct classes of teeth (incisors, canines, premolars, and molars) and the acquisition of tribosphenic molars facilitated precise occlusion between the teeth early in mammal evolution. Despite the evolutionary and ecological importance of distinct classes of teeth with unique cusp, crest, and basin m...

How developmental modifications produce key innovations, which subsequently allow for rapid diversification of a clade into new adaptive zones, has received much attention. However, few studies have used a robust comparative framework to investigate the influence of evolutionary and developmental constraints on the origin of key innovations, such a...

Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying ci...

External genital organs are among the most recognizable sexually dimorphic characters. The penis and clitoris develop from the embryonic genital tubercle, an outgrowth at the anterior margin of the cloaca that undergoes an extensive period of development in male and female embryos prior to the onset of sexual differentiation. In mice, differentiati...

Mice possess two types of teeth that differ in their cusp patterns; incisors have one cusp and molars have multiple cusps. The patterning of these two types of teeth relies on fine-tuning of the reciprocal molecular signaling between dental epithelial and mesenchymal tissues during embryonic development. The AP-2 transcription factors, particularly...

Congenital anomalies of the external genitalia (CAEG) are a prevalent and serious public health concern with lifelong impacts on the urinary function, sexual health, fertility, tumor development, and psychosocial wellbeing of affected individuals. Complications of treatment are frequent, and data reflecting long-term outcomes in adulthood are limit...

Congenital anomalies of external genitalia affect approximately 1 in 125 live male births. Development of the genital tubercle, the precursor of the penis and clitoris, is regulated by the urethral plate epithelium, an endodermal signaling center. Signaling activity of the urethral plate is mediated by Sonic hedgehog (SHH), which coordinates outgro...

Mice possess two types of teeth that differ in their cusp patterns; incisors have one cusp and molars have multiple cusps. The patterning of these two types of teeth relies on fine-tuning of the reciprocal molecular signaling between dental epithelial and mesenchymal tissues during embryonic development. Here we show that the incisors are populated...

Urogenital tract abnormalities are among the most common congenital defects in humans. Male urogenital development requires Hedgehog-GLI signaling and testicular hormones, but how these pathways interact is unclear. We found that Gli3XtJ mutant mice exhibit cryptorchidism and hypospadias due to local effects of GLI3 loss and systemic effects of tes...

Cephalopod mollusks evolved numerous anatomical novelties, including arms and tentacles, but little is known about the developmental mechanisms underlying cephalopod limb evolution. Here we show that all three axes of cuttlefish limbs are patterned by the same signaling networks that act in vertebrates and arthropods, although they evolved limbs in...

In recent decades, there has been a rise of endocrine-related diseases and disorders, including an increased incidence of genital anomalies, low semen quality, adverse pregnancy outcomes, neurobehavioral disruption, endocrine-related cancers, earlier onset of breast development, obesity, and type 2 diabetes (UNEP and WHO, 2013). An example of incre...

The origin of extracellular digestion in metazoans was accompanied by structural and physiological alterations of the gut. These adaptations culminated in the differentiation of a novel digestive structure in jawed vertebrates, the stomach. Specific endoderm/mesenchyme signalling is required for stomach differentiation, involving the growth and tra...

Vertebrate estrogen receptors (ERs) perform numerous cell signaling and transcriptional regulatory functions. ERɑ (Esr1) and ERβ (Esr2) likely evolved from an ancestral receptor that duplicated and diverged at the protein and cis-regulatory levels, but the evolutionary history of ERs, including the timing of proposed duplications, remains unresolve...

Cephalopod mollusks evolved numerous anatomical innovations, including specialized arms and tentacles, but little is known about the developmental mechanisms underlying the evolution of cephalopod limbs. Here we report that all three axes of cuttlefish limbs are patterned by the same signaling networks that act in vertebrates and arthropods, althou...

Extended data

The evolution of snakes involved dramatic modifications to the ancestral lizard body plan. Limb loss and elongation of the trunk are hallmarks of snakes, although convergent evolution of limb-reduced and trunk-elongated forms occurred multiple times in snake-like lizards. Advanced snakes are completely limbless, but intermediate and basal snakes ha...

X-ray microcomputed tomography was used to reveal putative trematode metacercariae (Platyhelminthes: Digenea) located in cysts positioned at the base of the femora in a 100 myr agamid lizard preserved in Myanmar amber. The cysts are characterized and compared with encysted metacercariae recovered from a similar location in an extant Anolis lizard....

Significance Disorders of sex development (DSDs) and some non-DSD human syndromes result in female genitourinary malformations. The mechanisms of genitourinary development are beginning to be understood in males; however, little is known about female lower genitourinary organogenesis. Prenatal exposure to excessive endogenous or exogenous androgens...

Limb reduction and loss are hallmarks of snake evolution. Although advanced snakes are completely limbless, basal and intermediate snakes retain pelvic girdles and small rudiments of the femur. Moreover, legs may have re-emerged in extinct snake lineages [1 • Caldwell M.W. • Lee M.S.Y. A snake with legs from the marine Cretaceous of the Middle Eas...

Vertebrates exhibit a remarkably broad variation in trunk and tail lengths. However, the evolutionary and developmental origins of this diversity remain largely unknown. Posterior Hox genes were proposed to be major players in trunk length diversification in vertebrates, but functional studies have so far failed to support this view. Here we identi...

Purpose: Lower urinary tract malformations are among the most common congenital anomalies in humans. Molecular genetic studies of mouse external genital development have begun to identify mechanisms that pattern the genital tubercle and orchestrate urethral tubulogenesis. The urethral plate epithelium is an endodermal signaling region that plays a...

The evolution of novel cell types led to the emergence of new tissues and organs during the diversification of animals. The origin of the chondrocyte, the cell type that synthesizes cartilage matrix, was central to the evolution of the vertebrate endoskeleton. Cartilage-like tissues also exist outside the vertebrates, although their relationship to...

Significance Birth defects of external genitalia occur at a striking frequency, affecting ∼1:250 live births. Congenital penile anomalies (CPAs) encompass a range of malformations, including failure of urethral tube closure (hypospadias), penile curvature (chordee), micropenis, and feminization of male genitalia. Both genetic anomalies and exposure...

The breadth of anatomical and functional diversity among amniote external gen-italia has led to uncertainty about the evolutionary origins of the phallus. In several lineages, including the tuatara, Sphenodon punctatus, adults lack an intro-mittent phallus, raising the possibility that the amniote ancestor lacked external genitalia and reproduced u...

Congenital anomalies frequently occur in organs that undergo tubulogenesis. Hypospadias is a urethral tube defect defined by mislocalized, oversized, or multiple openings of the penile urethra. Deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias in mice, in which the entire urethral plate is open along the ventral side of the penis....

Malformation of the urogenital tract represents a considerable paediatric burden, with many defects affecting the lower urinary tract (LUT), genital tubercle and associated structures. Understanding the molecular basis of such defects frequently draws on murine models. However, human anatomical terms do not always superimpose on the mouse, and the...

The segmental architecture of the arthropod head is one of the most controversial topics in the evolutionary developmental biology of arthropods. The deutocerebral (second) segment of the head is putatively homologous across Arthropoda, as inferred from the segmental distribution of the tripartite brain and the absence of Hox gene expression of thi...

The earliest known vertebrate copulatory organs are claspers, paired penis-like structures that are associated with evolution of internal fertilization and viviparity in Devonian placoderms. Today, only male chondrichthyans possess claspers, which extend from posterior pelvic fins and function as intromittent organs. Here we report that clasper dev...

Genital malformations occur at a high frequency in humans, affecting ~1:250 live births. The molecular mechanisms of external genital development are beginning to be identified; however, the origin of cells that give rise to external genitalia is unknown. Here we use cell lineage analysis to show that the genital tubercle, the precursor of the peni...

External genitalia are found in each of the major clades of amniotes. The phallus is an intromittent organ that functions to deliver sperm into the female reproductive tract for internal fertilization. The cellular and molecular genetic mechanisms of external genital development have begun to be elucidated from studies of the mouse genital tubercle...

Avian genitalia, particularly in waterfowl, are extremely diverse. Penis morphology varies among species, and penis length and elaboration are associated with the frequency of forced extra-pair copulations, yet the developmental mechanisms responsible for this variation are unknown. In addition, females have a small phallic structure that is homolo...

In most animals, reproduction by internal fertilization is facilitated by an intromittent organ, such as the penis in amniote vertebrates. Recent progress has begun to uncover the mechanisms of mammalian external genital development; however, comparatively little is known about the development of the reptilian penis and clitoris. Here, we describe...

In most amniotes, the intromittent organ is a single phallus; however, squamates (lizards, snakes, and amphisbaenians) have paired hemiphalluses. All amniotes studied to date initiate external genital development with the formation of paired genital swellings. In mammals, archosaurs, and turtles, these swellings merge to form a single genital tuber...

Within amniotes, external copulatory organs have undergone extensive morphological diversification. One of the most extreme examples is squamate (lizards and snakes) hemipenes, which are paired copulatory organs that extend from the lateral margins of the cloaca. Here, we describe the development of hemipenes in a basal snake, the ball python (Pyth...

Development of a phallus occurs in almost all amniotes; however, considerable variation in phallus morphology among different amniote lineages has contributed to the debate about their structural homology. Mammals are the only amniotes that form a closed urethral tube within the penis. In contrast, the phallus of reptiles and birds has an open uret...

Background: One of the most puzzling events in evolution is the reduction and loss of the phallus in birds. All birds reproduce by internal fertilization, but only ∼3% of birds have retained a phallus capable of intromission. A number of hypotheses have been proposed for the evolutionary mechanisms that drove phallus reduction; however, the underl...

Males and females generally have different finger proportions. In males, digit 2 is shorter than digit 4, but in females digit 2 is the same length or longer than digit 4. The second- to fourth-digit (2D:4D) ratio correlates with numerous sexually dimorphic behavioral and physiological conditions. Although correlational studies suggest that digit r...

Over the past decade, the genetics of external genital development have begun to be understood. Male and female external genitalia develop from the genital tubercle. The early tubercle has a superficial resemblance to the limb bud, but an important distinction is that the limb consists of only mesoderm and ectoderm, whereas the genital tubercle als...

Supplementary Figures S1–S3

During embryonic development, cells are instructed which position to occupy, they interpret these cues as differentiation programmes, and expand these patterns by growth. Sonic hedgehog (Shh) specifies positional identity in many organs; however, its role in growth is not well understood. In this study, we show that inactivation of Shh in external...

Malformations of the external genitalia are among the most common congenital anomalies in humans. The urogenital and anorectal sinuses develop from the embryonic cloaca, and the penis and clitoris develop from the genital tubercle. Within the genital tubercle, the endodermally derived urethral epithelium functions as an organizer and expresses soni...

In mammalian embryos, male and female external genitalia develop from the genital tubercle. Outgrowth of the genital tubercle is maintained by the urethral epithelium, and it has been reported that Fgf8 mediates this activity. To test directly whether Fgf8 is required for external genital development, we conditionally removed Fgf8 from the cloacal/...

Major advances in the molecular genetics, paleobiology, and the evolutionary developmental biology of vertebrate skeletogenesis have improved our understanding of the early evolution and development of the vertebrate skeleton. These studies have involved genetic analysis of model organisms, human genetics, comparative developmental studies of basal...

A classically identified "notochordal" cell population in the nucleus pulposus is thought to regulate disk homeostasis. However, the embryonic origin of these cells has been under dispute for >60 years. Here we provide the first direct evidence that all cell types in the adult mouse nucleus pulposus are derived from the embryonic notochord. Additio...

During vertebrate embryonic development, tissue patterning and differentiation are regulated by members of multigene families. Evolutionary expansion of these families is thought to have played a role in the evolution of anatomical complexity, including the origins of new cell and tissue types. A defining feature of vertebrates is an endoskeleton,...

Congenital malformations of anorectal and genitourinary (collectively, anogenital) organs occur at a high frequency in humans, however the lineage of cells that gives rise to anogenital organs remains poorly understood. The penile urethra has been reported to develop from two cell populations, with the proximal urethra developing from endoderm and...

Anthropoids in general and hominoids in particular exhibit differential adaptations in forearm and digital skeletal proportions to a diverse array of locomotor modes. Hox genes act as selector genes with spatially regulated expression patterns during development. Their expression in the forelimb appears to define modules that specify differential s...

Fkbp52 and Fkbp51 are tetratricopeptide repeat proteins found in steroid receptor complexes, and Fkbp51 is an androgen receptor (AR) target gene. Although in vitro studies suggest that Fkbp52 and Fkbp51 regulate hormone binding and/or subcellular trafficking of receptors, the roles of Fkbp52 and Fkbp51 in vivo have not been extensively investigated...

The evolutionary transition of fins to limbs involved development of a new suite of distal skeletal structures, the digits. During tetrapod limb development, genes at the 5' end of the HoxD cluster are expressed in two spatiotemporally distinct phases. In the first phase, Hoxd9-13 are activated sequentially and form nested domains along the anterop...

The origin of vertebrates was defined by evolution of a skeleton; however, little is known about the developmental mechanisms responsible for this landmark evolutionary innovation. In jawed vertebrates, cartilage matrix consists predominantly of type II collagen (Col2α1), whereas that of jawless fishes has long been thought to be noncollagenous. We...

The origin of paired appendages was a major evolutionary innovation for vertebrates, marking the first step towards fin- (and later limb-) driven locomotion. The earliest vertebrate fossils lack paired fins but have well-developed median fins, suggesting that the mechanisms of fin development were assembled first in the midline. Here we show that s...

Among mammals, modern cetaceans (whales, dolphins, and porpoises) are unusual in the absence of hind limbs. However, cetacean embryos do initiate hind-limb bud development. In dolphins, the bud arrests and degenerates around the fifth gestational week. Initial limb outgrowth in amniotes is maintained by two signaling centers, the apical ectodermal...

On Nov 4, 2008 this sequence version replaced gi:113206636.

Type II collagen is the major cartilage matrix protein in the jawed vertebrate skeleton. Lampreys and hagfishes, by contrast, are thought to have noncollagenous cartilage. This difference in skeletal structure has led to the hypothesis that the vertebrate common ancestor had a noncollagenous skeleton, with type II collagen becoming the predominant...

The vertebrate limb is a complex structure. The human forelimb, for example, contains 29 bones that are polarized along three axes: proximodistal (shoulder to fingertips), anteroposterior (thumb to small finger) and dorsoventral (back of hand to palm). The limb skeleton develops from a simple bud of undifferentiated mesenchyme that belies its ultim...

Vertebrates have evolved electrosensory receptors that detect electrical stimuli on the surface of the skin and transmit them somatotopically to the brain. In chondrichthyans, the electrosensory system is composed of a cephalic network of ampullary organs, known as the ampullae of Lorenzini, that can detect extremely weak electric fields during hun...

On Oct 17, 2006 this sequence version replaced gi:80973856.

On Oct 17, 2006 this sequence version replaced gi:80973858.

Development of external genitalia in mammalian embryos requires tight coordination of a complex series of morphogenetic events involving outgrowth, proximodistal and dorsoventral patterning, and epithelial tubulogenesis. Hypospadias is a congenital defect of the external genitalia that results from failure of urethral tube closure. Although this is...

The Eph family is the largest known group of structurally related receptor tyrosine kinases (RTKs). Each Eph receptor has a specific Ephrin ligand, and these function to define spatial boundaries during development. Analyses of EphA4 in mouse, chick, frog and zebrafish embryos have implicated this gene in a number of developmental processes, includ...

The incidence of congenital malformation of the urogenital system is second only to that of the cardiovascular system, yet comparatively little is known about the cellular and molecular mechanisms that regulate urogenital organogenesis. In this chapter, I review recent advances in the developmental biology of the external genitalia, and discuss the...

n order to identify developmental mechanisms involved in the origin and diversification of fins, we have undertaken a compara- tive analysis of fin development. Sharks, the most primitive group of extant vertebrates with paired fins, occupy a key phylo- genetic position as basal gnathostomes. As such, sharks provide a unique opportunity to study th...

We report the cDNA sequence and expression of a mouse homeobox gene, Dmbx1, from the PRD class and comparison to its human orthologue. The gene defines a new homeobox gene family, Dmbx, phylogenetically distinct from the Ptx, Alx, Prx Otx, Gsc, Otp and Pax gene families. The Dmbx1 gene is expressed in the developing mouse diencephalon, midbrain and...

External genital development begins with formation of paired genital swellings, which develop into the genital tubercle. Proximodistal outgrowth and axial patterning of the genital tubercle are coordinated to give rise to the penis or clitoris. The genital tubercle consists of lateral plate mesoderm, surface ectoderm, and endodermal urethral epithe...

Explanations of the patterns of vertebrate fin and limb evolution are improving as specific hypotheses based on molecular and developmental data are proposed and tested. Comparative analyses of gene expression patterns and functions in developing limbs, and morphological patterns in embryonic, adult and fossil limbs point to digit specification as...

The development of jaws was a critical event in vertebrate evolution because it ushered in a transition to a predatory lifestyle, but how this innovation came about has been a mystery. In the embryos of jawed vertebrates (gnathostomes), the jaw cartilage develops from the mandibular arch, where none of the Hox genes is expressed; if these are expre...

Over the past few years, our understanding of the evolution of limbs has been improved by important new discoveries in the fossil record. Additionally, rapid progress has been made in identifying the molecular basis of vertebrate limb development. It is now possible to integrate these two areas of research in order to identify the molecular develop...

A central feature of the tetrapod body plan is that two pairs of limbs develop at specific positions along the head-to-tail axis. However, the potential to form limbs in chick embryos is more widespread. This could have implications for understanding the basis of limb abnormalities. Here we extend the analysis to mouse embryos and examine systemati...

Vertebrate limbs are complicated structures. The genetic programme that directs their development is also proving to be complex, and trying to understand how it works is keeping developmental biologists busy. Three papers in Development1, 2, 3 now bring the molecular basis of limb development closer to hand, or rather to dHAND, a gene with a key ro...

SnR, twist and Fgf10 are expressed in presumptive limb territories of early chick embryos. When FGF-2/FGF-8 beads are implanted in chick flank, an ectopic limb develops and SnR is irreversibly activated as early as 1 h. Ectopic Fgf10 and twist expression are activated much later at 17 and 20 h, respectively. FGF-10 can also induce SnR, but much lat...