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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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Gene 'switch' clues us to origins of fine motor skills

A switch drives the supply of nerve cells going to our hands and feet. By identifying Hoxc9, we get an idea of the complexity and diversity of cells in our central nervous system.

Researchers have identified a genetic signature found exclusively in nerve cells that innervate muscles in our hands and feet. This gene signature is seeen in both mice and chickens, and involves coordination between multiple genes.

Digit-innervating motor neurons are fundamentally different from cells innervating nearby limb muscles. The discovery of an exclusive genetic signature, in hand and feet nerve cells, relates to the beginning of fine motor control of our extremities during evolution. The ability of a hand to grasp is one of our most essential adaptations.

Neuroscientists at Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute, along with those of New York University, led the study published in the journal Neuron.

"The emergence of hands, feet and digits — about 400 million years ago — represented a turning point in evolution. It helped the first land animals perform a variety of fine motor skills. But, while fine motor control has proven critical for survival for hundreds of millions of years, little is known about how nerve cells extend to the tips of our fingers and toes to make these skills possible."

Thomas M. Jessell PhD, Codirector, Columbia's Zuckerman Institute and senior author of the paper.

Researchers focused on motor neurons, a class of nerve cells that guide movement. Motor neurons target specific muscles, then relay signals from the brain telling those muscles how to move. The motor neurons that guide movement of the digits are called digit-innervating motor neurons.

"When we began this research, we were simply looking to compare key molecular features — namely gene activity — in motor neurons that supply different muscles in the leg," said Alana Mendelsohn, an MD/PhD candidate at Columbia and the paper's first author. "Instead, it soon became clear that the pattern of gene activity in the digit-innervating motor neurons in the foot was strikingly different compared to activity of motor neurons that innervate the more proximal [situated nearer to the center] muscles of the limb."

Specifically, Mendelsohn saw that motor neurons that supply both hands and feet did not produce a molecule called retinoic acid.

"One of the hallmark features of motor neurons is that they require retinoic acid for their growth and development," said Mendelsohn. "But, for some reason, digit-innervating motor neurons aren't producing it."

In fact, experiments reveal that retinoic acid, in digit-innervating motor neurons, is harmful. When the team introduced retinoic-acid into mouse and chick embryos, digit-innervating motor neurons stopped developing.

To investigate, Columbia researchers teamed up with Jeremy Dasen PhD, a former post-doctoral fellow with Dr. Jessell and now professor of neuroscience at the NYU Neuroscience Institute and an expert in the development and evolution of motor circuits.

Together, Dasen and Jessell hypothesize that key to innervating digitmotor neurons, may be Hox genes. Hox genes drive the growth and development of the nervous system and other systems.

In a series of experiments conducted at various stages of chick and mouse development, researchers identified Hoxc8 and Hoxc9, in the Hox gene family, both being required for development of motor neurons that supply the hand.

Surprisingly, although high levels of Hoxc9 is detrimental to limb-innervating motor neurons, the hand requires Hoxc9 — although at lower levels.

"The low levels of Hoxc9 appeared to be particularly important," said Dr. Jessell, who is also the Claire Tow Professor of Motor Neuron Disorders in the departments of neuroscience and biochemistry and molecular biophysics at Columbia University Medical Center. "Hoxc9 activity was high enough to prevent the production of retinoic acid (which would have been harmful) but low enough to still allow for the production of other proteins that we think are also necessary for the complete formation of digit-innervating motor neurons."

Moving forward, researchers hope to identify more in the suite of genes and proteins involved in digit-innervating motor neuron development. Also, they want to further investigate how the nervous system adapts to the emergence of digits over evolutionary history.

•Genes identified with selective expression in digit-innervating motor neurons
•Digit-innervating motor neurons do not synthesize retinoid acid
•Digit-innervating motor neurons express a distinct Hox gene repertoire
•Divergent Hox and retinoid code can specify digit-innervating motor neurons
The establishment of spinal motor neuron subclass diversity is achieved through developmental programs that are aligned with the organization of muscle targets in the limb. The evolutionary emergence of digits represents a specialized adaptation of limb morphology, yet it remains unclear how the specification of digit-innervating motor neuron subtypes parallels the elaboration of digits. We show that digit-innervating motor neurons can be defined by selective gene markers and distinguished from other LMC neurons by the expression of a variant Hox gene repertoire and by the failure to express a key enzyme involved in retinoic acid synthesis. This divergent developmental program is sufficient to induce the specification of digit-innervating motor neurons, emphasizing the specialized status of digit control in the evolution of skilled motor behaviors. Our findings suggest that the emergence of digits in the limb is matched by distinct mechanisms for specifying motor neurons that innervate digit muscles.

motor neuron, spinal cord, cell identity, development, Hox proteins, retinoid signaling, digits, motor control

This paper is titled: "Divergent hox coding and evasion of retinoid signaling specifies motor neurons innervating digit muscles."

This research was supported by The National Institutes of Health (R01 NS062822, R01 NS033245), the Brain Research Foundation, the Harold and Leila Y. Mathers Foundation, Project A.L.S. and the Howard Hughes Medical Institute.

The authors report no financial or other conflicts of interest.

Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute brings together an extraordinary group of world-class scientists and scholars to pursue the most urgent and exciting challenge of our time: understanding the brain and mind. A deeper understanding of the brain promises to transform human health and society. From effective treatments for disorders like Alzheimer's, Parkinson's, depression and autism to advances in fields as fundamental as computer science, economics, law, the arts and social policy, the potential for humanity is staggering. To learn more, visit: zuckermaninstitute.columbia.edu.

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Feb 21, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

For some unknow reason, retinoic acid, in digit-innervating motor neurons, is harmful.
Image Credit: studyblue.com



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