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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Developmental Biology - Neonatal Stroke

Strokes in Babies Surprisingly Common

Stroke affects 1 in 4,000 babies in the first month of life....

Our brain's frontline defender is our immune system cells or microglia. These cells make up 10% to 15% of all cells found in the brain. But their origins have been hotly debated. Chia-Yi "Alex" Kuan MD PhD, University of Virginia (UVA), has now discovered many microglia were previously white blood cells or monocytes.
During brain development - and in response to infant strokes - monocytes undergo an amazing conversion into microglia to protect the brain.

"Most people believe blood monocytes only flood into the brain after injury to prevent further damage, and then die - or somehow exit the brain. Some believe both exist in parallel with the other. Our results reveal many microglial cells actually originate from blood monocytes, both in normal development and after newborn brain injury," explains Kuan. The research is published in the scientific journal Science Advances.

The Brain's Immune Defenders

To explore the origins of our brain's immune defenses, Kuan and colleagues developed an innovative mouse model allowing his team to trace microglia from origin and throughout mouse brain development.

They were surprised to find many monocytes transform into microglia during the course of brain development. Prior to this discovery, science widely believed microglia did not arise from monocytes. Using a process called fate mapping. Kuan's team was able to reveal microglia's secret origins, seeing that monocytes rush to respond to neonatal stroke.
Neonatal strokes are interruptions in blood flow to an infant's brain in the first 28 days following birth. They have a wide variety of causes, from blood clots to developmental abnormalities.

Common symptoms include:
seizures and/or extreme sleepiness.

In some cases there are no symptoms - until much later in life when a child may develop speech difficulties and/or balance problems resulting from an undiagnosed brain injury.

In damaging strokes, Kuan found, there is an initial rush of monocytes, which gradually transform into microglia. This lasts at least 62 days after an initial stroke event. Some of these monocytes ultimately remain reprogrammed as microglia and become permanent defense cells within the brain.

The research invites new questions: "Can monocyte descended microglia impair brain development in infants who suffer newborn stroke and lead to neurological deficits? Can these former 'monocytes' be manipulated to improve outcomes of newborn brain injury? These fascinating questions beg for more research, explains Hong-Ru Chen PhD, first author of the new study.

Whether monocytes contribute to the brain microglial pool in development or after brain injury remains contentious. To address this issue, we generated CCR2-CreER mice to track monocyte derivatives in a tamoxifen-inducible manner. This method labeled Ly6Chi and Ly6Clo monocytes after tamoxifen dosing and detected a surge of perivascular macrophages before blood-brain barrier breakdown in adult stroke. When dosed by tamoxifen at embryonic day 17 (E17), this method captured fetal hematopoietic cells at E18, subdural Ki67+ ameboid cells at postnatal day 2 (P2), and perivascular microglia, leptomeningeal macrophages, and Iba1+Tmem119+P2RY12+ parenchymal microglia in selective brain regions at P24. Furthermore, this fate mapping strategy revealed an acute influx of monocytes after neonatal stroke, which gradually transformed into a ramified morphology and expressed microglial marker genes (Sall1, Tmem119, and P2RY12) for at least 62 days after injury. These results suggest an underappreciated level of monocyte-to-microglia transition in development and after neonatal stroke.

Hong-Ru Chen, Yu-Yo Sun, Ching-Wen Chen, Yi-Min Kuo, Irena S. Kuan, Zheng-Rong Tiger Li, Jonah C. Short-Miller, Marchelle R. Smucker and Chia-Yi Kuan.

The research was supported by National Institutes of Health grants NS095064, NS100419, NS108763 and NS106592. Hong-Ru Chen was supported by American Heart Association postdoctoral fellowship 18POST34080334.

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Sep 9 2020   Fetal Timeline   Maternal Timeline   News

Four Movies are available to download, depicting aspects of monocyte/microglia adaptation.
CREDIT The Authors.

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