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Today, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than 1 million visitors each month. The field of early embryology has grown to include the identification of the stem cell as not only critical to organogenesis in the embryo, but equally critical to organ function and repair in the adult human. The identification and understanding of genetic malfunction, inflammatory responses, and the progression in chronic disease, begins with a grounding in primary cellular and systemic functions manifested in the study of the early embryo.

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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Aug 11, 2014

Neurons in the developing brains of embryonic mice are guided by a simple
birth order rule that allows them to find and form their proper connections.

 






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Brain cells arrange themselves by birth order

Generating retinal ganglion cells — the axon cells that extend into the centers of our brain and give us "sight," — seems to depend on the timing of "who came first?"

Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple birth order rule that allows them to find and form their proper connections.

The study is published online July 31 in Cell Reports.

"Nothing about brain wiring is haphazard," said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego.


A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development.

The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection.


The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur.


To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice.

These cells connect the eyes and brain.


Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as "sight," as well as other light-influenced physiological processes, such as the effect of light on mood.

Scientists tagged RGCs and watched where they directed their axons during development of the growing embryo. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in embryo development while others (such as those controlling eye movements) are created in the later embryo.


The study's main finding is that RGCs created early in the sequence of brain cell division make a lot of connections to other neurons — and a lot of mistakes.

These mistakes are correct by repositioning or removing an axon. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors.


"The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate," said Jessica Osterhout, a doctoral student in biology and the study's lead author. "It seems to all boil down to birthdate."


The idea that timing is important for cell differentiation is a classic principle of developmental biology.

This study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring.


In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness.

Huberman:"We want to know if in diseases such as autism, neurons are made out of order and as a result get confused about which connections to make."

  • Highlights
    •Retinal axons innervate their targets over a broad time frame
  • •Functionally distinct RGCs employ different axon target matching strategies
  • •Birthdate and timing of axon arrival predict targeting strategy
  • •Sequential axon arrival may be a general mechanism for assembling complex circuits

Summary
How axons select their appropriate targets in the brain remains poorly understood. Here, we explore the cellular mechanisms of axon target matching in the developing visual system by comparing four transgenic mouse lines, each with a different population of genetically labeled retinal ganglion cells (RGCs) that connect to unique combinations of brain targets. We find that the time when an RGC axon arrives in the brain is correlated with its target selection strategy. Early-born, early-arriving RGC axons initially innervate multiple targets. Subsequently, most of those connections are removed. By contrast, later-born, later-arriving RGC axons are highly accurate in their initial target choices. These data reveal the diversity of cellular mechanisms that mammalian CNS axons use to pick their targets and highlight the key role of birthdate and outgrowth timing in influencing this precision. Timing-based mechanisms may underlie the assembly of the other sensory pathways and complex neural circuitry in the brain.

Co-authors include Rana El-Danaf and Phong Nguyen, both at UC San Diego.

Funding for the study was provided, in part, by the National Institutes of Health's National Eye Institute (grant R01-EY022157), The E. Matilda Ziegler Foundation for the Blind, Inc. and, The Pew Charitable Trusts.

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