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Welcome to The Visible Embryo, a comprehensive educational resource on human development from conception to birth.

The Visible Embryo provides visual references for changes in fetal development throughout pregnancy and can be navigated via fetal development or maternal changes.

The National Institutes of Child Health and Human Development awarded Phase I and Phase II Small Business Innovative Research Grants to develop The Visible Embryo. Initally designed to evaluate the internet as a teaching tool for first year medical students, The Visible Embryo is linked to over 600 educational institutions and is viewed by more than one million visitors each month.

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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Cochlea - Wikipedia

(LEFT) Hair cells of mice missing only Hey2 are neatly lined up in four rows
(RIGHT) Hair cells of mice missing Hey1 AND Hey2 are completely disorganized.
(WHITE ARROWS) Hairlike projections (bright pink) can be disoriented as well.
Image Credit: Angelika Doetzlhofer, professor, Neuroscience, Johns Hopkins School of Medicine,


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Ear 'hair' cells need precise alignment to work

Our inner ear is lined with 'hair' cells that translate sound waves into electrical impulses. These impulses are carried to the brain to be interpreted as individual sounds. But if the arrangement of ear 'hair' cells is disordered, impulses are disorganized and our hearing is impaired — or lost. 

Neuroscientists at Johns Hopkins have discovered the "molecular brakes" that time the creation and placement of inner ear 'hair' cells. "Hey1 and Hey2 act as brakes to prevent hair cell generation until the time is right [and therefore their placement correct]. Without them, the hair cells end up disorganized and dysfunctional," says Angelika Doetzlhofer, Ph.D., and assistant professor of neuroscience at the Johns Hopkins School of Medicine. A summary of her research is published in The Journal of Neuroscience.

The cochlea is a coiled, fluid-filled structure bordered by a flexible membrane which vibrates when hit by sound waves. Vibrations pass through the cochlea fluid and are transferred by specialized 'hair' cells lining it in four precise rows — into impulses sent to the brain. The 'hair' cell name comes from a single hairlike projection on each cell surface.

During fetal development, "parent cells" [cells that are the source of other cells] within the cochlea gradually change (differentiate) into hair cells in a precisely timed sequence, starting at the base of the cochlea and progressing toward its tip. The signaling protein Sonic Hedgehog is known to be released by nearby nerve cells in a time and space-dependent pattern as well — a pattern that matches that of hair cell differentiation or change.

Doetzlhofer and Ana Benito Gonzalez, postdoctoral fellow, bred mice whose inner ear cells were missing Hey1 and Hey2, two genes known to be active in the parent cells of hair cells - but turned off in hair cells themselves.

Doetzlhofer and Gonzalez found that without the Hey1 and Hey2 genes, hair cells were generated too early and were arranged in abnormal patterns. There were either too many or too few rows of hair cells, and often their hairlike projections were deformed.

"While these mice didn't live long enough for us to test their hearing, we know from other studies that mice with disorganized hair cell patterns have serious hearing problems," explained Doetzlhofer. Further experiments demonstrated the role of Sonic Hedgehog in regulating these key Hey1 and Hey2 genes.

"Hey1 and Hey2 stop the parent cells from turning into hair cells until the time is right. Sonic Hedgehog applies the 'brakes,' then slowly releases pressure on those brakes as the cochlea grows. If the brakes stop working, the hair cells are generated too early and end up misaligned."

Angelika Doetzlhofer, Ph.D., assistant professor, neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland

Doetzlhofer adds that Sonic Hedgehog along with Hey1 and Hey2 are found in many other types of parent cells throughout a developing nervous system. Therefore, these three components may play similar roles in timing the generation of other types of cells and should be explored.

Mechano-sensory hair cells (HCs), housed in the inner ear cochlea, are critical for the perception of sound. In the mammalian cochlea, differentiation of HCs occurs in a striking basal-to-apical and medial-to-lateral gradient, which is thought to ensure correct patterning and proper function of the auditory sensory epithelium. Recent studies have revealed that Hedgehog signaling opposes HC differentiation and is critical for the establishment of the graded pattern of auditory HC differentiation. However, how Hedgehog signaling interferes with HC differentiation is unknown. Here, we provide evidence that in the murine cochlea, Hey1 and Hey2 control the spatiotemporal pattern of HC differentiation downstream of Hedgehog signaling. It has been recently shown that HEY1 and HEY2, two highly redundant HES-related transcriptional repressors, are highly expressed in supporting cell (SC) and HC progenitors (prosensory cells), but their prosensory function remained untested. Using a conditional double knock-out strategy, we demonstrate that prosensory cells form and proliferate properly in the absence of Hey1 and Hey2 but differentiate prematurely because of precocious upregulation of the pro-HC factor Atoh1. Moreover, we demonstrate that prosensory-specific expression of Hey1 and Hey2 and its subsequent graded downregulation is controlled by Hedgehog signaling in a largely FGFR-dependent manner. In summary, our study reveals a critical role for Hey1 and Hey2 in prosensory cell maintenance and identifies Hedgehog signaling as a novel upstream regulator of their prosensory function in the mammalian cochlea. The regulatory mechanism described here might be a broadly applied mechanism for controlling progenitor behavior in the central and peripheral nervous system.

This work was supported by grants from the Whitehall Foundation (2010-05-81) and the National Institute on Deafness and other Communication Disorders (F32DC013477, DC005211).

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