The isthmic organizer, or isthmus organizer, also known as the midbrain−hindbrain boundary (MHB), is a secondary organizer region that develops at the junction of the

midbrain The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

and

metencephalon The metencephalon is the embryonic part of the hindbrain that differentiates into the pons and the cerebellum. It contains a portion of the fourth ventricle and the trigeminal nerve (CN V), abducens nerve (CN VI), facial nerve (CN VII), an ...

(embryonic

hindbrain The hindbrain, rhombencephalon (shaped like a rhombus) is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Met ...

). The MHB expresses

signaling molecules In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...

that regulate the differentiation and patterning of the adjacent neuroepithelium. This allows for the development of the

and

as well as the specification of

neuronal A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...

subtypes in these regions.Siegelbaum, Steven A., and A. James Hudspeth. Principles of neural science. Eds. Eric R. Kandel, James H. Schwartz, and Thomas M. Jessell. Vol. 5. New York: McGraw-hill, 2013. The fact that the MHB is sufficient for the development of the mid and hindbrain was shown in an

experiment An experiment is a procedure carried out to support or refute a hypothesis, or determine the efficacy or likelihood of something previously untried. Experiments provide insight into cause-and-effect by demonstrating what outcome occurs whe ...

where

quail Quail is a collective name for several genera of mid-sized birds generally placed in the order Galliformes. The collective noun for a group of quail is a flock, covey, or bevy. Old World quail are placed in the family Phasianidae, and New ...

MHB cells transplanted into the

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...

of a chick were able to induce an ectopic midbrain and

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

Development of the isthmus (MHB)

The development and location of the MHB is mediated by the

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

'' Otx2'' and '' Gbx2''. ''Otx2'' is expressed in the

anterior Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position pro ...

neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...

and cells in the posterior neural tube express ''Gbx2''. These two homeodomain transcription factors are activated by '' Irx1'' and then cross inhibit one another in the developing

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS). This leads to the creation of a defined boundary that becomes the isthmic organizer region after the neural tube closes.

Signaling molecules

The usual combined expression pattern of all involved

is necessary for the formation and maintenance of the MHB as well as the development of the midbrain and cerebellum. The following three signaling molecules act in an interconnected network to set up and maintain the MHB. Loss of any one of them leads to not only decreased expression of the other two but will also lead to partial or complete loss of the midbrain and hindbrain.

Fgf8

The interaction between ''Otx2'' and ''Gbx2'' at the MHB results in the expression of '' fibroblast growth factor 8 (Fgf8)''. Out of the known

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

of ''Fgf8'', ''Fgf8a'' and ''Fgf8b'' have been shown to be expressed at the isthmic organizer with ''Fgf8b'' being prevalent. ''Fgf8'' expression leads to the activation of '' En1'' in cells that express both ''Irx1'' and ''Otx2''. Fgf8 was shown to be an organizing molecule in the MHB through an experiment where an Fgf8-loaded bead was placed on a more anterior region of the neural tube. This resulted in the formation of a new ectopic MHB and showed that Fgf8 could mimic the activity of the MHB to induce the formation of midbrain and hindbrain structures from the anterior tissues. Fgf8 signaling at the MHB combined with ''Otx2'' expression induces

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

differentiation in the midbrain. On the other hand, when Fgf8 expression spreads into the ''Gbx2'' expressing hindbrain, it leads to serotonergic neuron differentiation. Later on in

embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...

, ''Fgf8'' expression localizes to the

rostral Rostral may refer to: Anatomy * Rostral (anatomical term), situated toward the oral or nasal region * Rostral bone, in ceratopsian dinosaurs * Rostral organ, of certain fish * Rostral scale The rostral scale, or rostral, in snakes and other sca ...

most ''Gbx2'' expressing cells (caudal region of the MHB) in the neural tube.Wnt1'' is mainly expressed in the entire midbrain (''Otx2'' expressing cells) at first. Once the midbrain/hindbrain boundary has formed, ''Wnt1'' expression localizes to the roof plate of the neural tube and to the posterior region of the midbrain. At the MHB, Wnt1 plays a role in cell proliferation and also maintains the ''FGF8'' expression.

Engrailed-1

The transcription factor ''En1'' is expressed in the MHB. In cells that express both ''Otx2'' and ''Irx1'', ''En1'' is activated by Fgf8 signaling. ''En1'' expression in cells that express both ''Pax2'' and ''Otx2'' leads to a midbrain identity/fate.

References

{{reflist Developmental neuroscience