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EMBRYONIC SIGNALS

SIGNALS WHICH MEDIATE EMBRYONIC DEVELOPMENT

     Early embryos face the daunting task of forming a complex body.  Cells like these of an early starfish embryo, must be able to form a starfish.

The cells below must be able to form the body of a primitive chordate (a lancelet).
STARFISH
The cells in the following image must be prepared to form an adult frog.
NEURAL
How can a few embryonic cells, all of which have the exact same set of genes, organize a body and form very different structures such as eyes, hearts, limbs, and livers?  One of the important factors in this process is the set of signal molecules which inform cells of where they are in a developing body and give them instructions as to which genes they should activate.  A large number of developmental processes are mediated through a small number of gene families which have been highly conserved in animals.  Sponges possess homologs of most of the signaling molecules(Wnt, TGF-beta, Hedgehog, receptor tyrosine kinase, Jak/STAT, and Notch) and cell adhesion molecules which metazoan animals use to produce their complex body forms (Nichols, 2006). Cnidarians and bilaterans, for example,  share a number of developmental genes such as forkhead, emx, aristaless, goosecoid, brachury, wnt, and nanos (Galliot, 2000).

 

Patterns of similarity in the timing of the gene classes used during embryonic development between mammals and insects indicate a conservation of ancestral mechanisms for the control of embryonic development (Wagner, 2005).

THE WNT FAMILY

     The Wnt gene family encodes a set of extracellular signals known from C.elegans through humans and were first identified as causing the wingless phenotype in Drosophila (Kelly, 1995).   The molecular mechanisms of Wnt signaling have been conserved between invertebrates and vertebrates (Saint-Jeannet, 1997).  The ancestral Wnt proteins had undergone duplication to produce a multigene family before the split of coelomate lineages.  Wnt1 through Wnt7 originated before this split.  Early in vertebrate evolution, additional duplications occurred (Sidow, 1992).  Tunicates use Wnt and Frizzled (the receptor for Wnt) signaling in development, and Wnt5 functions in the development of the notochord (Hotta, 2003).  Some human WNT genes (such as WNT 14 and 15) are more similar to WNT genes of flies and hagfish to those of other human WNT genes, indicating that the duplications which produced these different Wnt gene lineages occurred early in vertebrate evolution (Bergstein, 1997).

    Although some WNT genes are expressed in adult tissues and improper expression of WNT genes has been identified as a factor in some breast cancers, the primary function of the Wnt family  is the regulation of embryonic development, especially that of the nervous system.  WNT proteins are secreted during the development of the brain, kidneys, limbs, somites, and mammary glands.   Wnt8b is first expressed at gastrulation.   (Kelly, 1995). Gastrulation in a starfish is depicted below.

GASTRULA

 In flies, Dpp functions with wingless in the formation of the heart tube.  Their vertebrate counterparts (bone morphogenetic proteins and Wnt/Wg respectively) function in the formation of vertebrate embryonic hearts as well, suggesting that many of the molecular mechanisms of heart formation are conserved in coelomate animals (Nakamura, 2003).

     In the embryo, WNT is a dorsal signal which opposes the ventral signaling of sonic hedgehog. The dorsal nerve tube and ectoderm send WNT signals while the ventral notochord secretes sonic hedgehog.  In dorsal somites, WNT signaling induces growth arrest specific gene 1 (Gas1) which antagonizes the action of sonic hedgehog (Lee, 2001).   The neural tube and notochord of a frog embryo is depicted below.

NOTOCHORD

Wnt-1 and Wnt-3a functions in the differentiation of neural crest cells and in establishing a dorso-ventral axis in the neural tube (Saint-Jeannet, 1997). The use of Wnt to establish the dorsal/ventral body poles is important in the embryology of vertebrates. This signaling mechanism is not yet known in more primitive chordates ( Holland, 2002).

Wnt-4 functions in converting kidney mesenchyme into the epithelium of the nephron during the development of the kidney (Saint-Jeannet, 1997).  Wnt3a is involved in establishing the borders of somites (Rida, 2004). 

     Ectopic expression of Wnt genes can cause a duplication of the developing axis in frogs, resulting in double heads or even complete replicas of the longitudinal axis.  Wnt is required for insect segmentation and the development of mammalian brains.  The cells of a the brain in an embryonic pig are depicted in the following image.

LAYERS

Wnt mutations are known to cause breast cancer in mice but this has not been demonstrated in humans (Nuss, 1992).

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 1; WNT1

WNT1 is also known as oncogene int1.  It is involved in mammary development and some breast cancers.  Cells of a breast cancer are depicted in the following image.

BREAST CANCER

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 2; WNT2

WNT2 is expressed in the thalamus and may have a role in autism.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 2B; WNT2B

WNT2B is expressed in a variety of adult tissues.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 3; WNT3

WNT3 functions in neuron and growth cone development.  The following image is of the neurons extending into the developing leg of a pig embryo.

NERVE

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 3A; WNT3A

WNT3A is expressed in the placenta, adult lung, spleen, prostate, various regions of the brain, and is involved in hematopoeisis.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 4; WNT4

WNT4 is expressed in nephrons and proliferating mammary tissue in pregnancy.  Increased expression increases the expression of DAX1, a gene which can cause sex reversal.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 5A; WNT5A

WNT5A is expressed in the developing CNS, limbs, and face.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 5B; WNT5B

WNT5B is expressed in the fetal brain and other tissues.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 6; WNT6

WNT6 is expressed in the brain, testis, and some tumors.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 7A; WNT7A

WNT7A is expressed along the anterior-posterior axis of the female reproductive tract and is involved in the development of the uterus.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 7B; WNT7B

WNT7B levels increase in some breast cancers.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 8A; WNT8A

WNT8A is expressed in the developing brain, especially in the thalamus and hypothalamus.  The following image (on the right) is the developing brain of a pig embryo.

BRAIN

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 10A; WNT10A

WNT10A levels are highest in the placenta, fetal kidney, and fetal spleen.  Expression levels are lower in adult tissues although they can be raised in some tumors.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 10B; WNT10B

WNT10B levels are increased in some breast cancers.  This gene may be involved in adipose differentiation.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 11; WNT11

WNT11 is expressed in ureters, the perichondrium, lungs, urinary tract, and reproductive tissues.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 14; WNT14

WNT14 and WNT15 are more similar to hagfish and Drosophila proteins than to other members of the gene family found in humans.  WNT14 is expressed in the synovial joints of limbs.

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 15; WNT15

 

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 16; WNT16

WNT16 levels are increased in some leukemias.

 

FRIZZLED, (Wnt Receptors)

The Frizzled gene family consists of seven-path transmembrane receptors and which bind to Wg/Wnt.  Humans have 12 members of the Frizzled family, flies have five, and C.elegans has 3 (Hotta, 2003).  Disheveled is a cytoplasmic protein which is affected by Frizzled (Hotta, 2003)..

 

 


TGFβ FAMILY

TGFβ is an important growth factor whose inappropriate expression has been linked to a number of cancers.  TGFβ also plays a role embryonic development, such as in the development of the primordial germ cells which migrate from the allantois throughout the body to reach the gonads (Ara, 203).  A large number of related genes form the TGFβ gene family which is known in both invertebrates and vertebrates.  Many of these genes are important signals in embryonic development, such as Xnr3 which is a signal needed for the induction of nervous tissue. (Harland, 2000).

     The members of TGF-β superfamily are located on 8 chromosomes, frequently in areas which are associated with connective tissue and skeletal disorders (Dickinson, 1990).

The differentiation of heart tissue in vertebrates involves the actions of  bone morphogenetic proteins, TGF-β, FGFs, and Wnt (Nakamura, 2003).

      In frogs, 2 groups of TGF-β family members function in development.  One group, including activin and Vg1 induces the formation of mesoderm, including structures such as the notochord and muscle.  The second group are the BMP proteins involved in the dorsoventral differentiation of mesoderm and neurectoderm (Iemura, 1998).  The notochord and neural tissue of a developing frog are depicted below.

NOTOCHORD

     The TGFβ family includes bone morphogenetic proteins (BMPs) and cartilage-derived morphogenetic protein (CDMP).  BMPs are the vertebrate homologs of decapentaplegic genes in Drosophila (Manouvrier-Hanu, 1999) and a number of genes are known in mammals forming 3 subfamilies (Hino, 1996).  In flies, Dpp functions in the formation of the heart tube as do their vertebrate homologs, the BMPs (Nakamura, 2003).  Cardiac differentiation requires BMP2, BMP4, and BMP7 (Mohun, 1997).  In gastrulation, the Spemann organizer induces neurectoderm and mesoderm through signals which are classified as doralizing signals and general mesendoderm inducers.  The TGF-B family members active the Nodal/activin pathway as inducers of mesendoderm while Wnt family members send dorsalizing signals (Yamamoto, 2003).

     Early exposure of embryonic stem cells to BMP4 promotes them to adopt an epidermal fate rather than a neural fate.  In later stages of neuron precursors, the differing concentrations of BMP4 affects the differentiation of neurons to autonomic or sensory fates  (Mizuseki, 2003).  BMP2 induces neuroepithelial cells to differentiate into astrocytes rather than neurons (Nakashima, 2001). 

     In bilateral animals, dpp/BMP2/4 genes function in establishing a dorsal/ventral axis during development.  Homologs of this gene probably predated the evolution of bilateral animals, given the existence of a homolog in radially symmetrical coral where it expressed in a region near the blastopore.  This gene in a radially symmetrical animals can mimic the effects its bilateran homologs when inserted into Drosophila (Hayward, 2002).  Genes such as DPP/BMP4 and SOG/Chordin are conserved in protostomes and deuterostomes (flies and vertebrates, respectively).  In both flies and vertebrates, asymmetry in the oocyte affects the expression of dpp/BMP4  (Ferguson, 1996).    A homolog of Chordin which is so important in vertebrate development has been discovered in Hydra (Rentzsch, 2007). Tunicate larvae express a BMP protein during embryological development in a pattern similar to vertebrates (Miya, 1996).

     In zebrafish, swirl/BMP2 is required for dorsoventral patterning, like BMP4 in mice (but unlike BMP2 in mice).  In swirl mutants, the notochord and somites (both dorsal structures) are larger while ventral structures (such as blood and urinary structures) are absent.  The somites of a developing chick are visible in the image below on either side of the spinal cord.

SOMITES

BMPs/GDFs bind to a number of receptors (ALK2, 3, and 6; BMPR11, ACTRs) to activate Smad cytoplasmic proteins.  Smad1/Smad4 travels to the nucleus where it induces the differentiation into epidermal fates through genes such as msx1,vent, and Gata1.

Noggin, follistatin, chordin, Xnr3, and Cerberus block the action of BMPs (Weinstein, 1999; Kishimoto, 1997). 

 

TGF B FAMILY

Members of the TGFβ family induce the formation of different neurons in the dorsal spinal cord (Liem, 1997).

TRANSFORMING GROWTH FACTOR b1; TGFB1

TGFB1 promotes cell proliferation, differentiation, and wound healing.  Its expression is increased in Duchenne muscular dystrophy, kidney disease, and many cancers.

 

TRANSFORMING GROWTH FACTOR b2; TGFB2

TGFB2 is expressed in the eyes and some tumors.

 

TRANSFORMING GROWTH FACTOR b3; TGFB3

TGFB3 is involved in the fusion of the secondary palate.  It is expressed in the myometrium of the uterus and is overexpressed in some uterine cancers.

 

GROWTH/DIFFERENTIATION FACTOR 1; GDF1

GDF1 is expressed in the primitive node and neural tubes of early embryos.  It is also involved in the establishment of left/right asymmetry.  The following image is of the developing neural tube of a frog.

NEURAL TUBE

GROWTH/DIFFERENTIATION FACTOR 2; GDF2

GDF2 is a bone morphogenetic protein that is expressed in endothelial cells, Kupffer cells, the fetal septum, and fetal spinal cord.

 

GROWTH/DIFFERENTIATION FACTOR 3; GDF3

GDF3 is a bone morphogenetic protein.

 

GROWTH/DIFFERENTIATION FACTOR 5; GDF5

GDF5 is involved in skeletal development.  Mutations cause brachydactyly and chondroplasia.

 

GROWTH/DIFFERENTIATION FACTOR 8; GDF8

GDF8 is also known as myostatin and controls muscle mass.

 

GROWTH/DIFFERENTIATION FACTOR 9; GDF9

GDF9 is involved in oocyte growth and follicle development.  An oocyte and its surrounding follicular cells are depicted in the following image.

OVA

GROWTH/DIFFERENTIATION FACTOR 10; GDF10

GDF10 is also known as bone morphogenetic protein 3B.

 

GROWTH/DIFFERENTIATION FACTOR 11; GDF11

GDF11 is expressed in neurons.

 

Bone morphogenetic proteins 2 through 7 are members of the TGF family.

BONE MORPHOGENETIC PROTEIN 1; BMP1

BMP1 processes collagen and chordin.  It is the vertebrate homolog of the gene tolloid in Drosophila.

 

BONE MORPHOGENETIC PROTEIN 2; BMP2

BMP2 can cause apoptosis. BMP2 induces neuroepithelial cells to differentiate into astrocytes rather than neurons.  (Nakashima, 2001)

 

BONE MORPHOGENETIC PROTEIN 3; BMP3

 

BONE MORPHOGENETIC PROTEIN 4; BMP4

BMP4 is expressed in bone, during limb development, and during fracture repair.  The developing limb of an embryonic pig is depicted below.

LIMB

BONE MORPHOGENETIC PROTEIN 5; BMP5

BMP5 mutations in animals cause abnormalities in fracture repair and lung problems.

 

BONE MORPHOGENETIC PROTEIN 6; BMP6

BMP6 affects osteoblasts.

 

 BONE MORPHOGENETIC PROTEIN 7; BMP7

The formation of neural tissue in embryos requires events occurring before the formation of Henson’s node such as the expression of Fgf3, Bmp4, and Bmp7 (Wilson, 2000).

 

BONE MORPHOGENETIC PROTEIN 15; BMP15

BMP15 is expressed in follicular development and is important for female fertility.  It may be one of the factors which determines the infertility of Turner Syndrome females.

 

BONE MORPHOGENETIC PROTEIN, PLACENTAL

Placental BMP is expressed in the placenta and prostate.

 

The gene squint is a member of the TGFβ family which is required for the function of the organizer region of the dorsal mesoderm and for the differentiation of mesoderm and endoderm.  It is expressed in the yolk syncytial layer (Feldman, 1998).

Since the first bat fossils (about 50 million years old) there have not been significant increases in the lengths of the digits which compose the bat wing mammals (Sears, 2006). During embryological development, the digits of the bat hand begin with lengths comparable to those in the hand of a mouse. Later in development the third, fourth, and fifth digits increase due to increased production of cartilage in these developing digits. The embryonic signalling protein Bmp2 is not only capable of stimulating the growth of cartilage and elongation of developing bat digits, this signal is produced in the bat hand in levels much higher than those of the bat leg or of the mouse hand. An increased production of Bmp2 in the embryonic bat hand was probably a major factor in its specialization mammals (Sears, 2006).

 

ANTI-MULLERIAN HORMONE; AMH

Mutations in the anti-Mullerian hormone cause the persistence of the Mullerian ducts in males.  Mutant males are pseudohermpahrodites possessing both male and female organs.  The levels of this hormone in human infants is referred to distinguish between different causes of intersex individuals (OMIM). A domain of the Mullerian Inhibitin Substance gene, which causes the regression of the Mullerian ducts in males, is homologous to TGF b which inhibits growth in general (Cate, 1986).

 

 

TGF-B FAMILY INHIBITORS

A number of proteins are known which inhibit the signaling of TGF-B family members by binding to them extracellularly and inhibiting their interaction with receptors (Iemura, 1998).

 


 

HEDGEHOGS

     Hedgehog is one of the most important embryonic signaling molecules known.  The role of hedgehog homologs in the development of the nervous system and eyes in both vertebrates and invertebrates supports that these genetic mechanisms were in place in the ancestor of the coelomates.  The SHH protein is cleaved into two parts; one part binds cholesterol and diffuses to create a gradient in the developing limb of chicks.  On the right side of the heart, SHH is suppressed and this helps to establish the asymmetric structure of the heart.  Humans with SHH mutations are as likely to have their hearts on the right side of the sternum as the left.  SHH/IHH double mutant mice have linear heart tubes with no asymmetry (OMIM).  The first exon in the gene is the most invariant, suggesting it codes for a region of the protein with an essential conserved function (Zardoya, 1996). Shh can function as both a short-range and long-range morphogen (Sanz-Ezquerro, 2003).

  Shh is expressed in the notochord and floor plate, where it induces motor neuron differentiation and provides interneurons with positional information (Takatori, 2002; Mizuseki, 2003).   The neural tube and notochord of the developing chick are depicted below.

NOTOCHORD

     Sonic hedgehog from the urethral epithelium is required for the development of the external genetalia (Perriton, 2002). 

 

In the vertebrate nervous system, the medial and lateral ganglionic eminence stem cells produce cells which, after migration differentiate into either GABAergic neurons or oligodendrocytes.  In the spinal cord, the dorsal BMP signals induce the formation of astrocytes while the ventral Shh signals induce the formation of oligodendrocytes (Yung, 2002). 

     In vertebrates Shh controls the dorsal-ventral differentiation of the nervous system, the formation of left-right asymmetry, the formation of limb buds, and the development of the limb.  Shh expression in the limb activates transcription factors such as Hoxd-10 through Hoxd-13 which determine the development of the limb.  (Zardoya, 1996).  Interrupting Formin regulation of Shh can cause the absence of a thumb, fusion of 3rd and 4th digits, and radio-ulnar syntosis.  Shh is involved in the elongation of digits and misexpression of Shh can cause a duplication of the digits (Sanz-Ezquerro, 2003). The developing arm of an embryonic pig is depicted below.

ARM

     The repression of Sonic hedgehog in a restricted region of the posterior foregut causes the pancreas to develop.  Expansion of the area in which Shh is repressed can cause pancreatic tissue to develop in a larger area, including the stomach and duodenum (Kim, 1998).

   Tunicates possess 2 hedgehog genes resulting from a duplication  independent of that which produced multiple hedgehog genes in vertebrates (Takatori, 2002).

 

Sonic Hedgehog (7q36)

SHH

     Sonic Hedgehog is expressed during embryogenesis at Henson’s node, the floorplate of the neural tube, the early gut endoderm, the limb buds, and the notochord. 

     Null SHH mutations in mice cause abnormalities of the notochord, floorplate, neural tube (the absence of ventral-type cells), and respiratory tract.  In such mice, the vertebral column, most ribs, and the distal portions of the limbs are absent.  SHH overexpression results in the basal cell nevus syndrome, indicating that SHH may have a role in tumorgenesis.  SHH is required for the development of hair follicles in the embryo and may also be involved in the hair growth cycle in adults (if so, this would be the only known function of SHH in adults).  Shh mutations in humans can cause holoprosencephaly, polysyndactyly and even the existence of a single maxillary incisor (OMIM).

The reduction of Shh and the resulting death of neural crest cells are responsible for some of the abnormalities of fetal alcohol exposure (Ahlgren, 2002).

     Holoprosencephaly is a common embryonic defect (affecting 1/250 embryos) which usually results in miscarriage (and thus affects 1/15,000 live births).  It can cause a variety of defects ranging from the severe state of a single eye with a proboscis-like structure over it to milder defects including a single nostril, cleft lip, and a single central incisor.  Shh mutations cause holoprosencephaly in mice whose features include a single eye under a proboscis and the lack of many features of the face (Goodman, 2003).

CYCLOPIA

Shh promotes the differentiation of motor neurons and other ventral CNS tissues (Mizuseki, 2003).  Three zinc finger proteins (GLI1-3) are involved in the Hedgehog signaling pathway and are homologs of the segment polarity gene cubitus interruptus.  Interruptions in this pathway can cause polydactyly with up to 8 digits. (Manouvrier-Hanu, 1999).

 

Indian Hedgehog IHH (2p33)

     Indian hedgehog is expressed in adult tissues such as the kidney and liver and it is involved in the parathyroid hormone related protein pathway.  IHH functions in cartilage development and mutations can cause polydactyly, shortened limbs, and brachydactyly. (Manouvrier-Hanu, 1999; Sanz-Ezquerro, 2003; OMIM).  Indian hedgehog, BMP6, and gli are required for skeletal development and are expressed in growth plates until after puerty.  Ihh is not expressed in the formation of intermembranous bones (Iwasaki, 1997).

 

 

PATCHED (Hedgehog receptor)

Shh and its Patched (Ptc) receptor represent a major signaling pathway in the early differentiation of vertebrate limbs.  The arm buds of a pig embryo are depicted below.

(Sanz-Ezquerro, 2003).

ARM

OTHER EMBRYONIC SIGNALS

The Spemann organizer is an embryonic region which induces dorsal structures through secreted signals such as noggin, follistatin, and chordin (all three of which inactivate the ventral signaling molecule BMP4).  The notochord is derived from the Speman organizer and induces the formation of the neural tube’s floor plate and gives positional information to the developing somites through the secretion of Sonic Hedgehog (Matsui, 2000; Iemura, 1998). The neural crest cells express Snail and migrate in response to the Bmp expression of the overlying ectoderm and the Wnt 6 of the dorsal neural tube (Iulianella, 2003).  Neural crest cells migrated to form the dorsal root ganglion in the embryonic pig depicted below.

DORSAL ROOT GANGLION

FOLLISTATIN

Follistatin binds to activin, preventing its interaction with its receptors, and thus functions in the differentiation of mesoderm (Iemura, 1998).

Follistatin is produced by the Spenmann organizer and notochord promoting the formation of neural tissue by blocking the activity of activin (Hemmati-Brivaniou, 1994).

 

CHORDIN

     Just as there are genes which determine cell fate along a cranial-caudal axis, there are genes which control patterning along the dorsal ventral axis.  Genes such as DPP/BMP4 and SOG/Chordin are conserved in protostomes and deuterostomes (flies and vertebrates, respectively).  In both flies and vertebrates, asymmetry in the oocyte affects the expression of dpp/BMP4  and sog/chordin (and noggin, a second vertebrate homolog of sog) (Ferguson, 1996).

     The notochord and the floor plate also secrete a signal called Keilin which possesses chordin-like repeats (Matsui, 2000; Iemura, 1998).

 

NOGGIN

Noggin is an embryonic signal which inhibits the activity of BMP and TGF family members.  Mutant mice posses short limbs and lack joints in their paws.  Increased expression in frogs causes the development of large heads.  In humans, mutations cause the tarsal-coalition syndrome and other problems.  If mice are mutant for both noggin and chordin, they possess a single eye and nostril and lack jaws. 

Noggin induces the anterior brain but not the hindbrain or spinal cord (Lamb, 1993).

 

SLIT

     In 1993, it was demonstrated for the first time that a diffusible signal repelled axonal growth in the vertebrate brain (olfactory bulb axons, in this case).  In Drosophila, Slit proteins are chemorepellents of axon growth which are detected by 3 Roundabout (Robo) receptors.  In vertebrates, there are three Slit genes and 3 Robo genes which serve as their receptors.  They cause the chemorepulsion of axons of embryonic axons in that they can cause them to repel and collapse developing axons.   It seems that Slit proteins secreted from the septum is a repellent which guides the development of olfactory bulb axons, although not all studies support this (Patel, 2001; Battye, 1999; Nguyen-Ba-Charvet, 2002; Pini, 1993).

 

SLIT1

Slit is a Drosophila gene involved in the formation of the midline of the CNS.  EGF-like motifs are present in both human and fly genes.  In humans SLIT1 guides axons in the CNS.

 

SLIT2

Slit2 also functions in the CNS to guide axons.

 

SLIT3

Slit3 is primarily expressed in epithelial tissues.  Mutations cause congenital diaphragmatic hernia.

 

     The Notch family of receptor proteins are composed of several domains, one of which is similar to EGF and another is similar to cdc10/SW16/ankyrin sequences.  They are important mediators of cell-cell interactions during development.  Gene duplications had already produced several members of the Notch family before the division of coelomates (Maine, 1995).

     Notch-Delta signaling is required for the development of somites (Rida, 2004).  Hairy/E(spl) is activated by Notch and functions in the timing of somite development. (Rida, 2004).   Bilateran animals use the Notch family of receptors during embryonic development (represented in nematodes by LIN-12 and GLP-1).  These receptors bind the DSL family of transmembrane proteins which possess EGF domains.  The pattern of Notch signaling during neural development is similar in flies and vertebrates.  Notch also determines the differentiation of T cells into CD4 or CD8 cells and Notch mutations are involved in some leukemias (Robey, 1997).  The somites of a developing pig are depicted in the image

SOMITES

Cerebrus is a member of cysteine-knot secreted proteins which antagonize TGFβ family members.  Cerebrus binds to Nodal, BMP, and Wnt proteins (Piccolo, ?).

 

During gastrulation, the protein product of geminin (not known to be affiliated with other gene families) promotes the formation of neural tissue by suppressing BMP4 (Kroll, 1998).

 

Gelsolin is a dorsalizing factor in fish which performs various roles in development such as morphogenesis in tunicates, and the development of the nervous system, skeletal system, red blood cells, and mammary glands in mammals (Kanungo, 2003).

 

Neurotrophin 3 functions in the differentiation of cholinergic neurons.  Developing cholinergic neurons express two related receptor tyrosine kinases, TrkA and C (Brodski, 2000).

 

Mammals have a homolog of Not named for its role in the formation of the notochord in frogs (Ploughinec, 2004).

Retinoic acid is an important embryonic signal in establishing the anterior/posterior axis of the chordate body plan. Increased levels of retinoic acid causes the cranial migration of Hox1 expression which causes the homeotic increase in areas with a posterior fate (Canestro, 2007). The genes which are required for retinoic acid production (Aldh1a, Cyp26 and Rar) are known in non-chordate deuterostomes (Canestro, 2007).